liu.seSök publikationer i DiVA
Ändra sökning
Avgränsa sökresultatet
123 51 - 100 av 123
RefereraExporteraLänk till träfflistan
Permanent länk
Referera
Referensformat
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Träffar per sida
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sortering
  • Standard (Relevans)
  • Författare A-Ö
  • Författare Ö-A
  • Titel A-Ö
  • Titel Ö-A
  • Publikationstyp A-Ö
  • Publikationstyp Ö-A
  • Äldst först
  • Nyast först
  • Skapad (Äldst först)
  • Skapad (Nyast först)
  • Senast uppdaterad (Äldst först)
  • Senast uppdaterad (Nyast först)
  • Disputationsdatum (tidigaste först)
  • Disputationsdatum (senaste först)
  • Standard (Relevans)
  • Författare A-Ö
  • Författare Ö-A
  • Titel A-Ö
  • Titel Ö-A
  • Publikationstyp A-Ö
  • Publikationstyp Ö-A
  • Äldst först
  • Nyast först
  • Skapad (Äldst först)
  • Skapad (Nyast först)
  • Senast uppdaterad (Äldst först)
  • Senast uppdaterad (Nyast först)
  • Disputationsdatum (tidigaste först)
  • Disputationsdatum (senaste först)
Markera
Maxantalet träffar du kan exportera från sökgränssnittet är 250. Vid större uttag använd dig av utsökningar.
  • 51.
    Jansson, Agneta
    et al.
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Carlsson, Jonas
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Olsson, Anette
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Storm, Petter
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Margolin, Sara
    Department of Oncology, Karolinska University Hospital/ Södersjukhuset, Stockholm, Sweden.
    Gunnarsson, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk genetik. Linköpings universitet, Hälsouniversitetet.
    Stenmark Askmalm, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Lindblom, Annika
    Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
    Persson, Bengt
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Stål, Olle
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    A new polymorphism in the coding region of exon four in HSD17B2 in relation to risk of sporadic and hereditary breast cancer2007Ingår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 106, nr 1, s. 57-64Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In situ synthesis of oestrogens is of great importance in the development and progression of breast cancer. 17β-hydroxysteroid dehydrogenase (17HSD) type 2 catalyses oxidation from oestradiol to oestrone, and thereby protects the breast epithelial cells from oestradiol. Low expression of 17HSD type 2 has been associated with decreased survival in breast cancer, but no studies have investigated the mechanism behind the low expression. The 17HSD type 2 gene (HSD17B2) was screened for mutations with Single Stranded Conformation Polymorphism (SSCP)-DNA sequencing in 59 sporadic breast cancer cases, 19 hereditary breast cancer cases and seven breast cancer cell lines. DNA samples from 226 healthy individuals were used to identify if changes were previously unknown polymorphisms. No mutation was detected and therefore mutations in HSD17B2 do not explain why some breast tumours exhibit low 17HSD type 2 expression. However, a previously unknown polymorphism was found in exon four (Met226Val). Using molecular modelling, we found that the substituted residue is located at the outer part of the steroid binding site, probably causing minor alterations in the substrate binding. We further studied if the polymorphism contributes to breast cancer susceptibility in a larger material, but did not find an increased risk in the group of 317 sporadic breast cancer patients, 188 breast cancer patients with two close relatives with breast cancer or 122 hereditary breast cancer patients, compared to the healthy control group. We suggest that the detected polymorphism does not contribute to a higher risk of developing breast cancer.

  • 52.
    Jansson, Agneta
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Delander, Lovisa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Gunnarsson, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Fornander, Tommy
    Karolinska University Hospital.
    Skoog, Lambert
    Karolinska University Hospital.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Ratio of 17HSD1 to 17HSD2 protein expression predicts the outcome of tamoxifen treatment in postmenopausal breast cancer patients.2009Ingår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 15, nr 10, s. 3610-3616Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PURPOSE: Estrogens have great significance in the development of breast cancer. After menopause, most estrogen biosynthesis is done in peripheral tissue, and the main enzymes involved in balancing the amount of estrone against estradiol are 17beta-hydroxysteroid dehydrogenases (17HSD). The aim of this study was to investigate the prognostic and tamoxifen predictive values of 17HSD1 and 17HSD2 expression. EXPERIMENTAL DESIGN: Tumors from low-risk breast cancer patients randomized to adjuvant tamoxifen therapy or no adjuvant treatment were analyzed with immunohistochemistry to investigate protein expression of 17HSD1 and 17HSD2 in 912 cases. All patients had lymph node-negative breast cancer and were postmenopausal at the time of diagnosis. RESULTS: Low 17HSD1 expression was associated with significant benefit from tamoxifen treatment among patients with estrogen receptor (ER)-positive tumors (P < 0.001). For patients with a 17HSD1 score not exceeding that of 17HSD2, tamoxifen increased the rate of distant recurrence-free survival (hazard ratio, 0.37; 95% confidence interval, 0.23-0.60) and breast cancer-specific survival (hazard ratio, 0.30; 95% confidence interval, 0.16-0.54), whereas no apparent effect was observed when the 17HSD1 score was higher than that of 17HSD2. The interaction was significant for both distant recurrence-free survival (P = 0.036) and breast cancer-specific survival (P = 0.014). In the cohort of systemically untreated patients, no prognostic importance was observed. CONCLUSIONS: This is the first report that clearly distinguishes between the prognostic and predictive importance of 17HSD1 and 17HSD2 in ER-positive breast cancer treated with or without tamoxifen. Our data suggest that the 17HSD1/17HSD2 ratio might be useful as a predictive factor for tamoxifen treatment in ER-positive breast cancer patients.

  • 53.
    Jansson, Agneta
    et al.
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Gunnarsson, Cecilia
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala.
    Cohen, Maja
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Sivik, Tove
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Stål, Olle
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    17β-hydroxysteroid dehydrogenase 14 affects estradiol levels in breast cancer cells and is a prognostic marker in estrogen receptor-positive breast cancer2006Ingår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 66, nr 23, s. 11471-11477Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Estrogens have an important role in the progression of breast cancer. The 17β-hydroxysteroid dehydrogenase (17HSD) family has been identified to be of significance in hormone-dependent tissues. 17HSD1 and 17HSD2 are the main 17HSD enzymes involved in breast cancer investigated this far, but it is possible that other hormone-regulating enzymes have a similar role. 17HSD5 and 17HSD12 are associated with sex steroid metabolism, and 17HSD14 is a newly discovered enzyme that may be involved in the estrogen balance. The mRNA expression of 17HSD5, 17HSD12, and 17HSD14 were analyzed in 131 breast cancer specimens by semiquantitative real-time PCR. The results were compared with recurrence-free survival and breast cancer-specific survival of the patients. The breast cancer cell lines MCF7, SKBR3, and ZR75-1 were transiently transfected with 17HSD14 to investigate any possible effect on estradiol levels. We found that high 17HSD5 was related to significantly higher risk of late relapse in estrogen receptor (ER)-positive patients remaining recurrence-free later than 5 years after diagnosis (P = 0.02). No relation to 17HSD12 expression was found, indicating that 17HSD12 is of minor importance in breast cancer. Patients with ER-positive tumors with high expression levels of 17HSD14 showed a significantly better prognosis about recurrence-free survival (P = 0.008) as well as breast cancer-specific survival (P = 0.01), confirmed by multivariate analysis (P = 0.04). Transfection of 17HSD14 in the human breast cancer cells MCF7 and SKBR3 significantly decreased the levels of estradiol, presenting an effect of high expression levels of the enzyme. ©2006 American Association for Cancer Research.

  • 54.
    Jansson, Agneta
    et al.
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Gunnarsson, Cecilia
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Stål, Olle
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Proliferative responses to altered 17β-hydroxysteroid dehydrogenase (17HSD) type 2 expression in human breast cancer cells are dependent on endogenous expression of 17HSD type 1 and the oestradiol receptors2006Ingår i: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 13, nr 3, s. 875-884Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The primary source of oestrogen in premenopausal women is the ovary but, after menopause, oestrogen biosynthesis in peripheral tissue is the exclusive site of formation. An enzyme group that affects the availability of active oestrogens is the 17β-hydroxysteroid dehydrogenase (17HSD) family. In breast cancer, 17HSD type 1 and type 2 have been mostly investigated and seem to be the principal 17HSD enzymes involved thus far. The question whether 17HSD type 1 or type 2 is of greatest importance in breast tumour development is still not clear. The aim of this study was to investigate how the loss of 17HSD type 2 expression, using siRNA in the non-tumour breast epithelial cells HMEC (human mammal epithelial cells) and MCF10A, and gain of 17HSD type 2 expression, using transient transfection in the breast cancer derived cell lines MCF7 and T47D, affect oestradiol conversion and proliferation rate measured as S-phase fraction. We further investigated how this was related to the endogenous expression of 17HSD type 1 and oestradiol receptors in the examined cell lines. The oestradiol level in the medium changed significantly in the MCF7 transfected cells and the siRNA-treated HMEC cells, but not in T47D or MCF10A. The S-phase fraction decreased in the 17HSD type 2-transfected MCF7 cells and the siRNA-treated HMEC cells. The results seemed to be dependent on the endogenous expression of 17HSD type 1 and the oestradiol receptors. In conclusion, we found that high or low levels of 17HSD type 2 affected the oestradiol concentration significantly. However, the response was dependent on the endogenous expression of 17HSD type 1. Expression of 17HSD type 1 seems to be dominant to 17HSD type 2. Therefore, it may be important to investigate a ratio between 17HSD type 1 and 17HSD type 2.

  • 55.
    Jerevall, Piiha-Lotta
    et al.
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Ahmadi, Ahmad
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för medicinsk cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Bergman, Malin
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Stål, Olle
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Wingren, Sten
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för medicinsk cellbiologi.
    Sulfotransferase1A1 and risk of postmenopausal breast cancer2005Ingår i: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 25, nr 3 C, s. 2515-2517Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The detoxification enzyme sulfotransferase1A1 (SULT1A1) is implicated in the inactivation of estrogens and the activation of promutagens andprocarcinogens. SULT1A1 activity varies among individuals, and this difference in phenotype is, in part, controlled by genetic polymorphism (Arg→His in codon 213). It is hypothesized that the His allele contributes to the risk of postmenopausal breast cancer. Frequencies of the Arg/His alleles were estimated in 229 postmenopausal breast cancer patients and 227 age-matched controls using a PCR-RFLP assay. Allele frequencies and genotype distributions were not statistically different between postmenopausal breast cancer patients and the population-based controls, i.e. neither of the alleles is associated with an increased risk of breast cancer in the present study.

  • 56.
    Jerevall, Piiha-Lotta
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Brommesson, Sara
    Lund University Hospital.
    Strand, Carina
    Lund University Hospital.
    Gruvberger-Saal, Sofia
    Lund University Hospital.
    Malmström, Per
    Lund University Hospital.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Wingren, Sten
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Fernö, Mårten
    Lund University Hospital.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Exploring the two-gene ratio in breast cancer – independent roles for HOXB13 and IL17BR in prediction of clinical outcome2008Ingår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 107, nr 2, s. 225-234Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The two-gene expression ratio HOXB13:IL17BR has been proposed to predict the outcome of tamoxifen-treated breast cancer patients. We intended to examine whether this ratio can predict the benefit of 5 years vs. 2 years of tamoxifen treatment of postmenopausal patients. A further objective was to investigate any prognostic effects of the ratio in systemically untreated premenopausal patients. Based on the current knowledge of HOXB13 and IL17BR, we hypothesized that these genes may have individual prognostic or predictive power.

    Patients and methods: Expression of HOXB13 and IL17BR were quantified by real-time PCR in tumors from 264 randomized postmenopausal patients and 93 systemically untreated premenopausal patients.

    Results: A high HOXB13:IL17BR ratio was associated with aggressive tumor characteristics, as were low levels of IL17BR alone. The ratio and HOXB13 alone predicted recurrence-free survival after endocrine treatment, with a benefit of prolonged treatment in estrogen receptor-positive patients correlated to a low ratio (recurrence rate ratio: RR=0.39; p=0.030), or low expression of HOXB13 (RR=0.37; p=0.015). No difference in recurrence-free survival was seen for the high ratio or high HOXB13 subgroups. The predictive value of HOXB13 and HOXB13:IL17BR was significant in multivariate analysis. In the systemically untreated cohort, only IL17BR showed independent prognostic significance.

    Conclusion: We conclude that the ratio or HOXB13 alone can predict the benefit of endocrine therapy, with a high ratio or a high expression rendering patients less likely to respond. We have also shown that IL17BR might be an independent prognostic factor in breast cancer.

  • 57.
    Jerevall, Piiha-Lotta
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Jansson, A.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Fornander, T.
    Karolinska University Hospital.
    Skoog, L.
    Karolinska University Hospital.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    HOXB13 protein expression predicts the benefit of tamoxifen treatment in breast cancer patients: in CANCER RESEARCH, vol 69, issue 2, Supplement 1, pp 358S-358S2009Ingår i: CANCER RESEARCH, 2009, Vol. 69, nr 2, s. 358S-358SKonferensbidrag (Refereegranskat)
    Abstract [en]

    Background: The two-gene expression ratio HOXB13:IL17BR, originally from a microarray analysis, has been shown to be indicative of clinical outcome in the setting of adjuvant tamoxifen monotherapy of breast cancer, with a high ratio associated with decreased disease-free survival. Analysis of a cohort of breast cancer patients randomized to 2 or 5 years of adjuvant tamoxifen therapy showed that the two-gene ratio and expression of the HOXB13 gene alone were predictive of the benefit of prolonged tamoxifen treatment. Patients with tumors expressing HOXB13 at high levels were unresponsive to prolonged adjuvant treatment, suggesting that this gene is involved in tamoxifen resistance. It is suggested that a high two-gene ratio may indicate impaired ER signaling, which is known to predict resistance to tamoxifen. To our knowledge, there are no studies investigating the HOXB13 protein levels in breast cancer.

    Methods: We have analyzed the protein expression of HOXB13 with immunohistochemistry in tumor samples from 912 postmenopausal node negative breast cancer patients randomized to 2 years of tamoxifen or no endocrine treatment. After 2 years, recurrence-free patients were randomized to 3 more years of tamoxifen, or no further therapy. This selection enabled us to investigate the treatment predictive value of HOXB13.

    Results: Data on HOXB13 protein expression were obtained from 866 patients (see table). Tamoxifen treated patients with estrogen receptor (ER) positive tumors expressing none or low levels of HOXB13 had a clear benefit from tamoxifen in terms of longer distant recurrence-free survival (hazard ratio (HR) 0.37, 95% CI 0.23-0.60, p=0.000048). However, for patients with a high or intermediate HOXB13 tumor expression, tamoxifen did not prolong the distant recurrence-free survival compared to the untreated patients (HR=0.83, 95% CI 0.45-1.54, p=0.55). The interaction between HOXB13 expression and benefit from tamoxifen was statistically significant (p=0.046). HOXB13 did not have any prognostic value among systemically untreated patients.

  • 58.
    Jerevall, Piiha-Lotta
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Jansson, Agneta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Fornander, Tommy
    Department of Oncology, Karolinska University Hospital.
    Skoog, Lambert
    Department of Clinical Pathology and Cytology, Karolinska University Hospital.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Predictive relevance of HOXB13 protein expression for tamoxifen benefit in breast cancer2010Ingår i: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 12, nr 4Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    ABSTRACT: INTRODUCTION: The HOXB13:IL17BR index has been identified to predict clinical outcome in the setting of adjuvant tamoxifen monotherapy of breast cancer. Further studies have shown that HOXB13 in particular can indicate benefit of prolonged tamoxifen treatment. Patients with high-expressing tumors did not benefit from prolonged treatment, suggesting that HOXB13 might be involved in tamoxifen resistance. No studies have been made regarding the HOXB13 protein levels in breast cancer. The aim of our study was to investigate whether tamoxifen benefit can be correlated to different levels of HOXB13 protein expression. METHODS: We used immunohistochemistry to analyze protein levels of HOXB13 in tumor samples from 912 postmenopausal node-negative breast cancer patients randomized to adjuvant tamoxifen therapy or no endocrine treatment. RESULTS: Tamoxifen-treated patients with estrogen receptor-positive tumors expressing none or low levels of HOXB13 had a clear benefit from tamoxifen in terms of longer distant recurrence-free survival (DRFS) (hazard ratio = 0.38, 95% confidence interval = 0.23 to 0.60, P = 0.000048). However, for patients with a high or intermediate HOXB13 tumor expression, tamoxifen did not prolong the DRFS compared with the untreated patients (hazard ratio = 0.88, 95% confidence interval = 0.47 to 1.65, P = 0.69). Interaction between HOXB13 expression and benefit from tamoxifen was statistically significant for DRFS (P = 0.035). No prognostic value could be ascribed to HOXB13 among systemically untreated patients. CONCLUSIONS: A high HOXB13 expression was associated with decreased benefit from tamoxifen, which indicates that HOXB13 protein level may be used as a predictive marker for tamoxifen treatment.

  • 59.
    Jerevall, Piiha-Lotta
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Jansson, Agneta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Källström, Ann-Christine
    Department of Surgery, Helsingborg hospital, Helsingborg, Sweden.
    Landberg, Göran
    Center for Molecular Pathology, Lund University, Malmö University hospital, Malmö, Sweden.
    Fernö, Mårten
    Divison of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Homeobox B13 protein expression in a randomized tamoxifen trial of premenopausal breast cancerManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Homeobox B13 (HOXB13), part of the two-gene expression index HOXB13:IL17BR, has proven its capacity as a predictive factor of tamoxifen benefit in breast cancer. HOXB13 mRNA expression, as well as protein levels, have shown predictive value in postmenopausal patients. High levels were associated with decreased tamoxifen benefit and may indicate endocrine resistance. Here, we have analyzed HOXB13 protein expression in premenopausal breast cancer. We quantified the levels of HOXB13 with immunohistochemistry in tumor samples from 487 patients on tissue microarrays. Patients were diagnosed with stage II invasive breast cancer and randomized to tamoxifen or no endocrine treatment. HOXB13 protein analysis was successful for 367 patients. Data were correlated with clinicopathological variables. Investigation of tamoxifen benefit in patients with tumors expressing estrogen receptor (ER) α, progesterone receptor, or both, showed that patients with high HOXB13 levels had benefit from tamoxifen (hazard ratio for recurrences 0.43, 95% CI: 0.28-1.01, p=0.053). Corresponding numbers for the low HOXB13 group were 0.69 (95% CI: 0.44-1.07, p=0.10). For further analysis, we stratified the patients based on tumor ERβ status, which may function as a modifier of the performance of HOXB13 as a treatment predictive factor. For the ERβ positive subset of patients, there was a tendency towards a low HOXB13 expression associated with a better tamoxifen response. However, an increased benefit from tamoxifen, in terms of a longer recurrence-free survival (RFS), was associated with high HOXB13 expression in the ERβ negative group. The interaction between HOXB13 and treatment effect for RFS in the ERβ-negative group was significant in a multivariate model (p=0.04). In conclusion, in our study cohort, ERβ seems to be an additional determinant to HOXB13 protein expression for endocrine treatment prediction in premenopausal breast cancer. To identify patients less likely to respond to tamoxifen therapy, both HOXB13 and ERβ status should be taken into account.

  • 60.
    Jerevall, Piiha-Lotta
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Ma, Xiai-Jun
    bioTheranostics, San Diego, CA, USA.
    Li, Hongying
    bioTheranostics, San Diego, CA, USA.
    Salunga, Ranelle
    Massachusetts General Hospital, USA.
    Kesty, Nicole C.
    bioTheranostics, 9640 Towne Centre Dr Suite 200, San Diego, CA 92121, USA.
    Erlander, Mark G.
    Karolinska Institute, Stockholm, Sweden.
    Sgroi, Dennis
    Harvard Medical School, Boston, MA, USA.
    Holmlund, Birgitta
    Karolinska Institute, Stockholm, Sweden.
    Skoog, Lambert
    Karolinska Institute, Stockholm, Sweden.
    Fornander, Tommy
    Karolinska Institute, Stockholm, Sweden.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Prognostic utility of HOXB13:IL17BR and Molecular Grade Index in early-stage breast cancer patients from the Stockholm trial2011Ingår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 104, nr 11, s. 1762-1769Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: A dichotomous index combining two gene expression assays, HOXB13:IL17BR (H:I) and molecular grade index (MGI), was developed to assess risk of recurrence in breast cancer patients. The study objective was to demonstrate the prognostic utility of the combined index in early-stage breast cancer.

    Methods: In a blinded retrospective analysis of 588 ER-positive tamoxifen-treated and untreated breast cancer patients from the randomized prospective Stockholm trial, H:I and MGI were measured using real-time RT-PCR. Association with patient outcome was evaluated by Kaplan-Meier analysis and Cox proportional hazard regression. A continuous risk index was developed using Cox modeling.

    Results: The dichotomous H:I+MGI was significantly associated with distant recurrence and breast cancer death. The >50% of tamoxifen-treated patients categorized as low-risk had <3% 10-year distant recurrence risk. A continuous risk model (Breast Cancer Index (BCI)) was developed with the tamoxifen-treated group and the prognostic performance tested in the untreated group was 53% of patients categorized as low-risk with an 8.3% 10-year distant recurrence risk.

    Conclusion: Retrospective analysis of this randomized, prospective trial cohort validated the prognostic utility of H:I+MGI and was used to develop and test a continuous risk model that enables prediction of distant recurrence risk at the patient level.

  • 61.
    Jirström, K
    et al.
    Division of Pathology Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden .
    Rydén, L
    Division of Pathology Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden .
    Anagnostaki, L
    Division of Pathology Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden .
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Stål, Olle
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Thorstenson, S
    Department of Pathology and Cytology, Kalmar County Hospital, Kalmar, Sweden .
    Chebil, G
    Department of Pathology, Helsingborg Hospital, Helsingborg, Sweden.
    Jönsson, P-E
    Department of Surgery, Helsingborg Hospital.
    Fernö, M
    Department of Oncology, Lund University Hospital, Lund, Sweden.
    Landberg, G
    Division of Pathology Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden .
    Pathology parameters and adjuvant tamoxifen response in a randomised premenopausal breast cancer trial2005Ingår i: Journal of Clinical Pathology, ISSN 0021-9746, E-ISSN 1472-4146, Vol. 58, nr 11, s. 1135-1142Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Subgroups of breast cancer that have an impaired response to endocrine treatment, despite hormone receptor positivity, are still poorly defined. Breast cancer can be subdivided according to standard pathological parameters including histological type, grade, and assessment of proliferation. These parameters are the net result of combinations of genetic alterations effecting tumour behaviour and could potentially reflect subtypes that respond differently to endocrine treatment.

    Aims: To investigate the usefulness of these parameters as predictors of the response to tamoxifen in premenopausal women with breast cancer.

    Materials/methods: Clinically established pathological parameters were assessed and related to the tamoxifen response in 500 available tumour specimens from 564 premenopausal patients with breast cancer randomised to either two years of tamoxifen or no treatment with 14 years of follow up. Proliferation was further evaluated by immunohistochemical Ki-67 expression.

    Results: Oestrogen receptor positive ductal carcinomas responded as expected to tamoxifen, whereas the difference in recurrence free survival between control and tamoxifen treated patients was less apparent in the relatively few lobular carcinomas. For histological grade, there was no obvious difference in treatment response between the groups. The relation between proliferation and tamoxifen response seemed to be more complex, with a clear response in tumours with high and low proliferation, whereas tumours with intermediate proliferation defined by Ki-67 responded more poorly.

    Conclusions: Clinically established pathology parameters seem to mirror the endocrine treatment response and could potentially be valuable in future treatment decisions for patients with breast cancer.

  • 62.
    Jirström, Karin
    et al.
    Division of Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden.
    Stendahl, Maria
    Division of Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden.
    Rydén, Lisa
    Division of Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden.
    Kronblad, Åsa
    Division of Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden.
    Bendahl, Pär-Ola
    Department of Oncology, University Hospital, Lund, Sweden.
    Stål, Olle
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Landberg, Göran
    Division of Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden.
    Adverse effect of adjuvant tamoxifen in premenopausal breast cancer with cyclin D1 gene amplification2005Ingår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 65, nr 17, s. 8009-8016Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cyclins D1 and A2 are cell cycle regulators that also have the ability to interact with the estrogen receptor (ER) and consequently interfere with antiestrogen treatment in breast cancer. Experimental data support this concept, but the clinical relevance needs to be further established. In this study, we evaluated cyclin D1 and A2 protein expression by immunohistochemistry and cyclin D1 gene (CCND1) amplification by fluorescence in situ hybridization in 500 primary breast cancers arranged in tissue microarrays. Patients had been randomized to 2 years of adjuvant tamoxifen or no treatment with a median follow-up of 14 years, allowing for subgroup analysis of treatment response defined by cyclin status. We found that both cyclin D1 and A2 protein overexpression was associated with an impaired tamoxifen response, although not significant in multivariate interaction analyses, whereas tamoxifen-treated patients with CCND1-amplified tumors had a substantially increased risk for disease recurrence after tamoxifen treatment in univariate analyses [relative risk (RR), 2.22; 95% confidence interval (95% CI), 0.94-5.26; P = 0.06] in contrast to nonamplified tumors (RR, 0.39; 95% CI, 0.23-0.65; P < 0.0001). Consequently, a highly significant interaction between tamoxifen treatment and CCND1 amplification could be shown regarding both recurrence-free survival (RR, 6.38; 95% CI, 2.29-17.78; P < 0.001) and overall survival (RR, 5.34; 95% CI, 1.84-15.51; P = 0.002), suggesting an agonistic effect of tamoxifen in ER-positive tumors. In node-positive patients, the disparate outcome according to gene amplification status was even more accentuated. In summary, our data implicate that despite a significant correlation to cyclin D1 protein expression, amplification status of the CCND1 gene seems a strong independent predictor of tamoxifen response, and possibly agonism, in premenopausal breast cancer.

  • 63.
    Jogi, Annika
    et al.
    Lund University, Malmo University Hospital, Department Lab Med, Centre Mol Pathol, SE-20502 Malmo, Sweden Lund University, CREATE Hlth Centre Translat Canc Research, SE-20502 Malmo, Sweden .
    Brennan, Donal J
    University Coll Dublin, Sch Biomol and Biomed Science, Conway Institute, Dublin 2, Ireland .
    Ryden, Lisa
    Lund University, Div Surg, Department Clin Science, SE-20502 Malmo, Sweden .
    Magnusson, Kristina
    Uppsala University, Department Genet and Pathol, Rudbeck Lab, Uppsala, Sweden .
    Ferno, Marten
    University Lund Hospital, Div Oncol, Department Clin Science, S-22185 Lund, Sweden .
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Borgquist, Signe
    University Lund Hospital, Div Oncol, Department Clin Science, S-22185 Lund, Sweden .
    Uhlen, Mathias
    AlbaNova University Centre, Royal Institute Technology, Department Biotechnol, Stockholm, Sweden .
    Landberg, Goran
    Lund University, Malmo University Hospital, Department Lab Med, Centre Mol Pathol, SE-20502 Malmo, Sweden .
    Pahlman, Sven
    Lund University, Malmo University Hospital, Department Lab Med, Centre Mol Pathol, SE-20502 Malmo, Sweden Lund University, CREATE Hlth Centre Translat Canc Research, SE-20502 Malmo, Sweden .
    Ponten, Fredrik
    Lund University, Div Surg, Department Clin Science, SE-20502 Malmo, Sweden .
    Jirstrom, Karin
    Lund University, Malmo University Hospital, Department Lab Med, Centre Mol Pathol, SE-20502 Malmo, Sweden Lund University, CREATE Hlth Centre Translat Canc Research, SE-20502 Malmo, Sweden .
    Nuclear expression of the RNA-binding protein RBM3 is associated with an improved clinical outcome in breast cancer2009Ingår i: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 22, nr 12, s. 1564-1574Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Single-strand RNA-binding proteins (RBPs) are involved in many aspects of RNA metabolism and in the regulation of gene transcription. The RBP RBM3 was recently suggested to be a proto-oncogene in colorectal cancer; however, such a role has not been corroborated by previous studies in the colon or other tumor types, and the prognostic implications of tumor-specific RBM3 expression remain unclear. Mono-specific antibodies against RBM3 were generated. Antibody specificity was confirmed using siRNA gene silencing, western blotting and immunohistochemistry on a panel of breast cancer cell lines. Using tissue microarrays and IHC, RBM3 protein expression was examined in 48 normal tissues and in 20 common cancers. Additional analysis in two independent breast cancer cohorts (n = 1016) with long-term follow-up was also carried out. RBM3 was upregulated in cancer compared to normal tissues. The nuclear expression of RBM3 in breast cancer was associated with low grade (Pandlt;0.001), small tumors (Pandlt;0.001), estrogen receptor (ER) positivity (Pandlt;0.001) and Ki-67 negativity (Pandlt;0.001) in both the breast cancer cohorts. An increased nuclear expression of RBM3 was associated with a prolonged overall and recurrence-free survival. The prognostic value was particularly pronounced in hormone receptor-positive tumors and remained significant in multivariate interaction analysis after controlling for tamoxifen treatment (HR: 0.49, 95% CI: 0.30-0.79, P = 0.004). These data strongly indicate that nuclear RBM3 is an independent favorable prognostic factor in breast cancer, and seems to have a specific role in ER-positive tumors.

  • 64.
    Johansson, Henrik J
    et al.
    Department Oncology-Pathology, Cancer Proteomics Mass spectrometry, Science for Life Laboratory, Karolinska Institutet, SE-171 65 Stockholm, Sweden.
    Sanchez, Betzabe C
    Department Oncology-Pathology, Cancer Proteomics Mass spectrometry, Science for Life Laboratory, Karolinska Institutet, SE-171 65 Stockholm, Sweden.
    Forshed, Jenny
    Department Oncology-Pathology, Cancer Proteomics Mass spectrometry, Science for Life Laboratory, Karolinska Institutet, SE-171 65 Stockholm, Sweden.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US. Linköpings universitet, Hälsouniversitetet.
    Fohlin, Helena
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Region Östergötland, Centrum för hälso- och vårdutveckling, Regionalt cancercentrum. Linköpings universitet, Hälsouniversitetet.
    Lewensohn, Rolf
    Department of Oncology, Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden.
    Hall, Per
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, Stockholm, 17177 Sweden.
    Bergh, Jonas
    Department Oncology-Pathology, Cancer Proteomics Mass spectrometry, Science for Life Laboratory, Karolinska Institutet, SE-171 65 Stockholm, Sweden.
    Lehtiö, Janne
    Department Oncology-Pathology, Cancer Proteomics Mass spectrometry, Science for Life Laboratory, Karolinska Institutet, SE-171 65 Stockholm, Sweden.
    Linderholm, Barbro K
    Department Oncology-Pathology, Cancer Proteomics Mass spectrometry, Science for Life Laboratory, Karolinska Institutet, SE-171 65 Stockholm, Sweden // Department of Oncology, Sahlgrenska Academy and University Hospital, SE-413 45 Gothenburg, Sweden.
    Proteomics profiling identify CAPS as a potential predictive marker of tamoxifen resistance in estrogen receptor positive breast cancer2015Ingår i: Clinical Proteomics, ISSN 1542-6416, E-ISSN 1559-0275, Vol. 12, nr 1, s. 8-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Despite the success of tamoxifen since its introduction, about one-third of patients with estrogen (ER) and/or progesterone receptor (PgR) - positive breast cancer (BC) do not benefit from therapy. Here, we aim to identify molecular mechanisms and protein biomarkers involved in tamoxifen resistance.

    RESULTS: Using iTRAQ and Immobilized pH gradient-isoelectric focusing (IPG-IEF) mass spectrometry based proteomics we compared tumors from 12 patients with early relapses (<2 years) and 12 responsive to therapy (relapse-free > 7 years). A panel of 13 proteins (TCEAL4, AZGP1, S100A10, ALDH6A1, AHNAK, FBP1, S100A4, HSP90AB1, PDXK, GFPT1, RAB21, MX1, CAPS) from the 3101 identified proteins, potentially separate relapse from non-relapse BC patients. The proteins in the panel are involved in processes such as calcium (Ca(2+)) signaling, metabolism, epithelial mesenchymal transition (EMT), metastasis and invasion. Validation of the highest expressed proteins in the relapse group identify high tumor levels of CAPS as predictive of tamoxifen response in a patient cohort receiving tamoxifen as only adjuvant therapy.

    CONCLUSIONS: This data implicate CAPS in tamoxifen resistance and as a potential predictive marker.

  • 65.
    Johansson, Henrik J.
    et al.
    Karolinska Institute, Sweden .
    Sanchez, Betzabe C.
    Karolinska Institute, Sweden .
    Mundt, Filip
    Karolinska Institute, Sweden .
    Forshed, Jenny
    Karolinska Institute, Sweden .
    Kovacs, Aniko
    University Hospital, Sweden .
    Panizza, Elena
    Karolinska Institute, Sweden .
    Hultin-Rosenberg, Lina
    Karolinska Institute, Sweden .
    Lundgren, Bo
    Stockholm University, Sweden .
    Martens, Ulf
    Stockholm University, Sweden .
    Mathe, Gyongyver
    University Hospital, Sweden .
    Yakhini, Zohar
    Agilent Labs, Israel Technion Israel Institute Technology, Israel .
    Helou, Khalil
    University Hospital, Sweden .
    Krawiec, Kamilla
    Karolinska University Hospital, Sweden .
    Kanter, Lena
    Karolinska Institute, Sweden .
    Hjerpe, Anders
    Karolinska Institute, Sweden .
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Linderholm, Barbro K.
    Karolinska Institute, Sweden University Hospital, Sweden .
    Lehtio, Janne
    Karolinska Institute, Sweden .
    Retinoic acid receptor alpha is associated with tamoxifen resistance in breast cancer2013Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 4, nr 3175Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    About one-third of oestrogen receptor alpha-positive breast cancer patients treated with tamoxifen relapse. Here we identify the nuclear receptor retinoic acid receptor alpha as a marker of tamoxifen resistance. Using quantitative mass spectrometry-based proteomics, we show that retinoic acid receptor alpha protein networks and levels differ in a tamoxifen-sensitive (MCF7) and a tamoxifen-resistant (LCC2) cell line. High intratumoural retinoic acid receptor alpha protein levels also correlate with reduced relapse-free survival in oestrogen receptor alpha-positive breast cancer patients treated with adjuvant tamoxifen solely. A similar retinoic acid receptor alpha expression pattern is seen in a comparable independent patient cohort. An oestrogen receptor alpha and retinoic acid receptor alpha ligand screening reveals that tamoxifen-resistant LCC2 cells have increased sensitivity to retinoic acid receptor alpha ligands and are less sensitive to oestrogen receptor alpha ligands compared with MCF7 cells. Our data indicate that retinoic acid receptor alpha may be a novel therapeutic target and a predictive factor for oestrogen receptor alpha-positive breast cancer patients treated with adjuvant tamoxifen.

  • 66.
    Johansson, Patrik
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Fohlin, Helena
    Arnesson, Lars-Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala.
    Dufmats, Monika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Nordenskjoeld, Kerstin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Improved survival for women with stage I breast cancer in south-east Sweden: A comparison between two time periods before and after increased use of adjuvant systemic therapy2009Ingår i: ACTA ONCOLOGICA, ISSN 0284-186X, Vol. 48, nr 4, s. 504-513Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose. Continuous minor steps of improvement in the management of breast cancer have resulted in decreased mortality rates during the last decades. The aim of this study was to compare the clinical outcome of patients with stage I breast cancer diagnosed during two time periods that differed with respect to adjuvant systemic therapy. Material and methods. The studied population consisted of all women 60 years of age, who were diagnosed breast cancer stage I between 1986 and 1999 in south-east Sweden, a total of 1 407 cases. The cohort was divided into two groups based on the management programmes of 1986 and 1992, hereafter referred to as Period 1 and Period 2. Before 1992 the only adjuvant systemic therapy recommended was tamoxifen for hormone receptor positive patients aged 50 years or older. During Period 2 the use of adjuvant treatment was extended to younger patients at high risk, identified by a high tumour S-phase fraction, with either hormonal or cytotoxic treatment. Results. The estimated distant recurrence-free survival rate was significantly higher during Period 2 than during Period 1 (p = 0.008). Subgroup analysis showed that the most evident reduction of distant recurrence risk was among hormone receptor-negative patients (HR = 0.58, 95% CI 0.31-1.09, p = 0.09) and among patients with a high tumour S-phase fraction (HR = 0.53, 0.30-0.93, p = 0.028). The risk reduction between the periods was still statistically significant in multivariate analysis when adjusting for different tumour characteristics and treatment modalities, indicating an influence of other factors not controlled for. One such factor may be the duration of tamoxifen treatment, which likely was more frequently five years during Period 2 than during Period 1. Conclusions. We conclude that the causes of the increase in distant recurrence free survival for women with breast cancer stage I are complex. The results support though that high-risk subgroups of stage I breast cancer patients did benefit from increased use of systemic therapy as a consequence of an updated management programme.

  • 67.
    Kallstrom, Ann-Christine
    et al.
    Helsingborg Hospital.
    Salme, Rebecka
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Ryden, Lisa
    Lund University.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Jonsson, Per-Ebbe
    Helsingborg Hospital.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    17 beta-Hydroxysteroid dehydrogenase type 1 as predictor of tamoxifen response in premenopausal breast cancer2010Ingår i: EUROPEAN JOURNAL OF CANCER, ISSN 0959-8049, Vol. 46, nr 5, s. 892-900Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    17 beta-Hydroxysteroid dehydrogenases (17HSDs) are involved in the local regulation of sex steroids. 17HSD1 converts oestrone (El) to the more potent oestradiol (E2) and 17HSD2 catalyses the reverse reaction. The aim of this study was to investigate the expression of these enzymes in premenopausal breast cancers and to analyse if they have any prognostic or tamoxifen predictive value. Premenopausal patients with invasive breast cancer, stage II (UICC), were randomised to either 2 years of adjuvant tamoxifen (n = 276) or no tamoxifen (n = 288). The median follow-up was 13.9 years (range 10.5-17.5). The expression of 17HSD1 and 17HSD2 was analysed with immunohistochemistry using tissue microarrays. The enzyme expression level (-/+/++/+++) was successfully determined in 396 and 373 tumours, respectively. Women with hormone-receptor positive tumours, with low levels (-/+/++) of 17HSD1, had a 43% reduced risk of recurrence, when treated with tamoxifen (Hazard Ratio (HR) = 0.57; 95% confidence interval (CI), 0.37-0.86; p = 0.0086). On the other hand high expression (+++) of 17HSD1 was associated with no significant difference between the two treatment arms (HR = 0.91; 95% CI, 0.43-1.95; p = 0.82). The interaction between 17HSD1 and tamoxifen was significant during the first 5 years of follow-up (p = 0.023). In the cohort of systemically untreated patients no prognostic importance was observed for 17HSD1. We found no predictive or prognostic value for 17HSD2. This is the first report of 17HSD1 in a cohort of premenopausal women with breast cancer randomised to tamoxifen. Our data suggest that 17HSD1 might be a predictive factor in this group of patients.

  • 68.
    Karlsson, E
    et al.
    Karolinska University Hospital.
    Waltersson, M A
    Karolinska University Hospital.
    Bostner, Josefine
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Perez-Tenorio, Gizeh
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Olsson, Birgit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Fornander, T
    Karolinska University Hospital.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Comprehensive Genomic and Transcriptomic Analysis of the 11q13 Amplicon in Breast Cancer in CANCER RESEARCH, vol 69, issue 24, pp 820S-821S2009Ingår i: CANCER RESEARCH, 2009, Vol. 69, nr 24, s. 820S-821SKonferensbidrag (Refereegranskat)
    Abstract [en]

    n/a

  • 69.
    Karlsson, Elin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Ahnström, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Bostner, Josefine
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Perez-Tenorio, Gizeh
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Olsson, Birgit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Hallbeck, Anna-Lotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    High-Resolution Genomic Analysis of the 11q13 Amplicon in Breast Cancers Identifies Synergy with 8p12 Amplification, Involving the mTOR Targets S6K2 and 4EBP12011Ingår i: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 50, nr 10, s. 775-787Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The chromosomal region 11q13 is amplified in 15-20% of breast cancers; an event not only associated with estrogen receptor (ER) expression but also implicated in resistance to endocrine therapy. Coamplifications of the 11q13 and 8p12 regions are common, suggesting synergy between the amplicons. The aim was to identify candidate oncogenes in the 11q13 region based on recurrent amplification patterns and correlations to mRNA expression levels. Furthermore, the 11q13/8p12 coamplification and its prognostic value, was evaluated at the DNA and the mRNA levels. Affymetrix 250K NspI arrays were used for whole-genome screening of DNA copy number changes in 29 breast tumors. To identify amplicon cores at 11q13 and 8p12, genomic identification of significant targets in cancer (GISTIC) was applied. The mRNA expression levels of candidate oncogenes in the amplicons [ RAD9A, RPS6KB2 (S6K2), CCND1, FGF19, FGF4, FGF3, PAK1, GAB2 (11q13); EIF4EBP1 (4EBP1), PPAPDC1B, and FGFR1 (8p12)] were evaluated using real-time PCR. Resulting data revealed three main amplification cores at 11q13. ER expression was associated with the central 11q13 amplification core, encompassing CCND1, whereas 8p12 amplification/gene expression correlated to S6K2 in a proximal 11q13 core. Amplification of 8p12 and high expression of 4EBP1 or FGFR1 was associated with a poor outcome in the group. In conclusion, single nucleotide polymorphism arrays have enabled mapping of the 11q13 amplicon in breast tumors with high resolution. A proximal 11q13 core including S6K2 was identified as involved in the coamplification/coexpression with 8p12, suggesting synergy between the mTOR targets S6K2 and 4EBP1 in breast cancer development and progression.

  • 70.
    Karlsson, Elin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Magic, Ivana
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Bostner, Josefine
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Dyrager, Christine
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Lysholm, Fredrik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Hallbeck, Anna-Lotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Lundström, Patrik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Revealing Different Roles of the mTOR-Targets S6K1 and S6K2 in Breast Cancer by Expression Profiling and Structural Analysis2015Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 12, s. e0145013-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    The AKT/mTORC1/S6K pathway is frequently overstimulated in breast cancer, constituting a promising therapeutic target. The benefit from mTOR inhibitors varies, likely as a consequence of tumour heterogeneity, and upregulation of several compensatory feed-back mechanisms. The mTORC1 downstream effectors S6K1, S6K2, and 4EBP1 are amplified and overexpressed in breast cancer, associated with a poor outcome and divergent endocrine treatment benefit. S6K1 and S6K2 share high sequence homology, but evidence of partly distinct biological functions is emerging. The aim of this work was to explore possible different roles and treatment target potentials of S6K1 and S6K2 in breast cancer.

    Materials and methods

    Whole-genome expression profiles were compared for breast tumours expressing high levels of S6K1, S6K2 or 4EBP1, using public datasets, as well as after in vitro siRNA downregulation of S6K1 and/or S6K2 in ZR751 breast cancer cells. In silico homology modelling of the S6K2 kinase domain was used to evaluate its possible structural divergences to S6K1.

    Results

    Genome expression profiles were highly different in S6K1 and S6K2 high tumours, whereas S6K2 and 4EBP1 profiles showed significant overlaps, both correlated to genes involved in cell cycle progression, among these the master regulator E2F1. S6K2 and 4EBP1 were inversely associated with IGF1 levels, and their prognostic value was shown to be restricted to tumours positive for IGFR and/or HER2. In vitro, S6K1 and S6K2 silencing resulted in upregulation of genes in the mTORC1 and mTORC2 complexes. Isoform-specific silencing also showed distinct patterns, e.g. S6K2 downregulation lead to upregulation of several cell cycle associated genes. Structural analyses of the S6K2 kinase domain showed unique structure patterns, deviating from those of S6K1, facilitating the development of isoform-specific inhibitors. Our data support emerging proposals of distinct biological features of S6K1 and S6K2, suggesting their importance as separate oncogenes and clinical markers, where specific targeting in different breast cancer subtypes could facilitate further individualised therapies.

  • 71.
    Karlsson, Elin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Pérez-Tenorio, Gizeh
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Amin, Risul
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Bostner, Josefine
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Skoog, Lambert
    Department of Pathology and Cytology, Karolinska University Hospital, Solna, Stockholm, Sweden.
    Fornander, Tommy
    Department of Oncology, Karolinska University Hospital, Stockholm South General Hospital, Stockholm, Sweden .
    Sgroi, Dennis C
    Department of Pathology, Molecular Pathology Research Unit, Massachusetts General Hospital, Boston, USA.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Hallbeck, Anna-Lotta
    Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    The mTOR effectors 4EBP1 and S6K2 are frequently coexpressed, and associated with a poor prognosis and endocrine resistance in breast cancer: a retrospective study including patients from the randomised Stockholm tamoxifen trials.2013Ingår i: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 15, nr 5, s. R96-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    INTRODUCTION: mTOR and its downstream effectors the 4E-binding protein 1 (4EBP1) and the p70 ribosomal S6 kinases (S6K1 and S6K2) are frequently upregulated in breast cancer, and assumed to be driving forces in tumourigenesis, in close connection with oestrogen receptor (ER) networks. Here, we investigated these factors as clinical markers in five different cohorts of breast cancer patients.

    METHODS: The prognostic significance of 4EBP1, S6K1 and S6K2 mRNA expression was assessed with real-time PCR in 93 tumours from the treatment randomised Stockholm trials, encompassing postmenopausal patients enrolled between 1976 and 1990. Three publicly available breast cancer cohorts were used to confirm the results. Furthermore, the predictive values of 4EBP1 and p4EBP1_S65 protein expression for both prognosis and endocrine treatment benefit were assessed by immunohistochemical analysis of 912 node-negative breast cancers from the Stockholm trials.

    RESULTS: S6K2 and 4EBP1 mRNA expression levels showed significant correlation and were associated with a poor outcome in all cohorts investigated. 4EBP1 protein was confirmed as an independent prognostic factor, especially in progesterone receptor (PgR)-expressing cancers. 4EBP1 protein expression was also associated with a poor response to endocrine treatment in the ER/PgR positive group. Cross-talk to genomic as well as non-genomic ER/PgR signalling may be involved and the results further support a combination of ER and mTOR signalling targeted therapies.

    CONCLUSION: This study suggests S6K2 and 4EBP1 as important factors for breast tumourigenesis, interplaying with hormone receptor signalling. We propose S6K2 and 4EBP1 as new potential clinical markers for prognosis and endocrine therapy response in breast cancer.

  • 72.
    Karlsson, Elin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Veenstra, Cynthia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Emin, Shad
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Dutta, Chhanda
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Perez-Tenorio, Gizeh
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Fornander, Tommy
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Loss of protein tyrosine phosphatase, non-receptor type 2 is associated with activation of AKT and tamoxifen resistance in breast cancer2015Ingår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 153, nr 1, s. 31-40Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Breast cancer is a heterogeneous disease and new clinical markers are needed to individualise disease management and therapy further. Alterations in the PI3K/AKT pathway, mainly PIK3CA mutations, have been shown frequently especially in the luminal breast cancer subtypes, suggesting a cross-talk between ER and PI3K/AKT. Aberrant PI3K/AKT signalling has been connected to poor response to anti-oestrogen therapies. In vitro studies have shown protein tyrosine phosphatase, non-receptor type 2 (PTPN2) as a previously unknown negative regulator of the PI3K/AKT pathway. Here, we evaluate possible genomic alterations in the PTPN2 gene and its potential as a new prognostic and treatment predictive marker for endocrine therapy benefit in breast cancer. PTPN2 gene copy number was assessed by real-time PCR in 215 tumour samples from a treatment randomised study consisting of postmenopausal patients diagnosed with stage II breast cancer 1976-1990. Corresponding mRNA expression levels of PTPN2 were evaluated in 86 available samples by the same methodology. Gene copy loss of PTPN2 was detected in 16 % (34/215) of the tumours and this was significantly correlated with lower levels of PTPN2 mRNA. PTPN2 gene loss and lower mRNA levels were associated with activation of AKT and a poor prognosis. Furthermore, PTPN2 gene loss was a significant predictive marker of poor benefit from tamoxifen treatment. In conclusion, genomic loss of PTPN2 may be a previously unknown mechanism of PI3K/AKT upregulation in breast cancer. PTPN2 status is a potential new clinical marker of endocrine treatment benefit which could guide further individualised therapies in breast cancer.

  • 73.
    Khoshnoud, Mahmoud R
    et al.
    Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Lofdahl, Britta
    Department of Pathology, Uppsala University Hospital, Sweden.
    Fohlin, Helena
    Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiskt centrum. Linköpings universitet, Hälsouniversitetet.
    Fornander, Tommy
    Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Skoog, Lambert
    Department of Pathology, Karolinska University Hospital, Stockholm, Sweden.
    Bergh, Jonas
    Cancer Center, Karolinska Institute, Stockholm Sweden and Medical Breast Unit, Christie Hospital, Manchester, UK.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Immunohistochemistry compared to cytosol assays for determination of estrogen receptor and prediction of the long-term effect of adjuvant tamoxifen2011Ingår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 126, nr 2, s. 421-430Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The purpose of this study is to compare immunohistochemistry (IHC) and cytosol-based assays for determination of estrogen receptor (ER) and prediction of response to adjuvant tamoxifen treatment in postmenopausal women with early-stage invasive breast cancer. The Stockholm Breast Cancer Study Group conducted a randomized trial during 1976 through 1990 comparing adjuvant tamoxifen versus control. The patients were stratified according to tumor size and lymph node status in high-risk and low-risk groups. In this study we evaluated 683 patients with “low risk” breast cancer (size ≤30 mm, lymph node-negative) for whom ER status had been determined by both the cytosol assays and IHC at one pathology laboratory. The median follow-up was 17 years. Six hundred eighty-three patients had tumors with ER determined by both methods, 536 (78.5%) were ER-positive by cytosol assays using the cutoff level at ≥0.05 fmol/μg DNA and 539 patients were ER-positive (79%) by IHC using the cutoff level at ≥10% cell stained. Thirty-nine tumors (5.7%) were ER-positive by cytosol but not by IHC, whereas the opposite pattern was found for 42 cases (6.1%). Only seven tumors had stained cells between 0 and 9% by IHC. The concordance between IHC and cytosol assays was high (88%). The kappa statistic was 0.65, 95% CI 0.58–0.72. Among patients classified as ER-negative no therapeutic benefit from tamoxifen was observed. Among patients with ER-expressing tumors, tamoxifen resulted in significantly better recurrence-free survival irrespective of the method (IHC: HR, 0.53, P < 0.001; cytosol: HR, 0.53, P < 0.001). The effect on overall survival was not statistically significant probably due to the limited sample size. Both IHC and cytosol assay accurately predict long-term response to adjuvant tamoxifen.

  • 74.
    Kok, Marleen
    et al.
    Netherlands Canc Inst, Dept Expt Therapy, Amsterdam, Netherlands.
    Holm-Wigerup, Caroline
    Lund Univ, Malmo Univ Hosp, Ctr Mol Pathol, Malmo, Sweden.
    Hauptmann, Michael
    Netherlands Canc Inst, Dept Bioinformat and Stat, Amsterdam, Netherlands.
    Michalides, Rob
    Netherlands Canc Inst, Dept Tumor Biol, Amsterdam, Netherlands.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Linn, Sabine
    Netherlands Canc Inst, Dept Mol Biol, Amsterdam, Netherlands.
    Landberg, Goran
    Univ Manchester, Breakthrough Breast Canc Res Unit, Sch Canc Enabling Sci and Technol,Christie NHS Fdn, Manchester Acad Hlth Sci Ctr,Paterson Inst Canc R, Manchester M20 4BX, Lancs, England.
    Estrogen Receptor-alpha Phosphorylation at Serine-118 and Tamoxifen Response in Breast Cancer2009Ingår i: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 101, nr 24, s. 1725-1729Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Although estrogen receptor-alpha (ER alpha) is a marker used to identify breast cancer patients most likely to benefit from endocrine therapy, approximately 50% of ER alpha-positive breast carcinomas are resistant to tamoxifen. Preclinical studies have shown that phosphorylation of ER alpha at serine-118 (ER alpha S118-P) is required for tamoxifen-mediated inhibition of ER alpha-induced gene expression. We evaluated the association between recurrence-free survival after tamoxifen treatment and ER alpha S118-P expression by use of Cox proportional hazards regression. Data were from 239 premenopausal patients with breast cancer who participated in a randomized trial of 2 years of adjuvant tamoxifen treatment vs no systemic treatment. ER alpha S118-P expression was assessed by immunohistochemistry and categorized by use of the Allred score (low expression = score of 0-6; high expression = score of 7-8). All statistical tests were two-sided. Compared with systemically untreated patients, we found evidence of a benefit from adjuvant tamoxifen among patients whose tumors had high ER alpha S118-P expression (23.7 recurrences per 1000 person-years versus 72.2 recurrences per 1000 person-years, hazard ratio [HR] of recurrence = 0.36, 95% confidence interval [CI] = 0.20 to 0.65) but not among patients whose tumors had low expression (51.0 recurrences per 1000 person-years versus 57.0 recurrences per 1000 person-years, HR of recurrence = 0.87, 95% CI = 0.51 to 1.48.

  • 75.
    Kok, Marleen
    et al.
    Netherlands Cancer Institute.
    Zwart, Wilbert
    Netherlands Cancer Institute.
    Holm, Caroline
    Lund University.
    Fles, Renske
    Netherlands Cancer Institute.
    Hauptmann, Michael
    Netherlands Cancer Institute.
    Vant Veer, LauraJ.
    Netherlands Cancer Institute.
    Wessels, Lodewyk F. A.
    Netherlands Cancer Institute.
    Neefjes, Jacques
    Netherlands Cancer Institute.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Linn, Sabine C.
    Netherlands Cancer Institute.
    Landberg, Goran
    Lund University.
    Michalides, Rob
    Netherlands Cancer Institute.
    PKA-induced phosphorylation of ER alpha at serine 305 and high PAK1 levels is associated with sensitivity to tamoxifen in ER-positive breast cancer2011Ingår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 125, nr 1Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Phosphorylation of estrogen receptor alpha at serine 305 (ER alpha S305-P) by protein kinase A (PKA) or p21-activated kinase 1 (PAK1) has experimentally been associated with tamoxifen sensitivity. Here, we investigated the clinical application of this knowledge to predict tamoxifen resistance in ER-positive breast cancer patients. Using immunohistochemistry, a score including PAK1 and co-expression of PKA and ER alpha S305-P (PKA/ER alpha S305-P) was developed on a training set consisting of 103 patients treated with tamoxifen for metastatic disease, and validated on 231 patients randomized between adjuvant tamoxifen or no treatment. In the training set, PAK1 levels were associated with tumor progression after tamoxifen (HR 1.57, 95% CI 0.99-2.48), as was co-expression of PKA and ER alpha S305-P (HR 2.00, 95% CI 1.14-3.52). In the validation set, a significant tamoxifen benefit was found among the 73% patients negative for PAK1 and PKA/ER alpha S305-P (HR 0.54, 95% CI 0.34-0.87), while others (27%) were likely to have no benefit from tamoxifen (HR 0.88, 95% 0.42-1.82). The test for interaction showed a significant difference in recurrence-free survival between groups defined by PAK1 and PKA/ER alpha S305-P (P = 0.037). Elevated PAK1 and PKA/ER alpha S305-P appeared to influence tamoxifen sensitivity. Both PAK1 and PKA/ER alpha S305-P levels were associated with sensitivity to tamoxifen in breast tumors and the combination of these variables should be considered in predicting tamoxifen benefit.

  • 76.
    Lehn, Sophie
    et al.
    Lund University, Sweden .
    Tobin, Nicholas P.
    Karolinska Institute, Sweden St Gorans University Hospital, Sweden .
    Sims, Andrew H.
    University of Edinburgh, Scotland .
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Jirstrom, Karin
    Lund University, Sweden .
    Axelson, Hakan
    Lund University, Sweden .
    Landberg, Goran
    University of Gothenburg, Sweden University of Manchester, England .
    Decreased expression of Yes-associated protein is associated with outcome in the luminal A breast cancer subgroup and with an impaired tamoxifen response2014Ingår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 14, nr 119Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Yes-associated protein (YAP1) is frequently reported to function as an oncogene in many types of cancer, but in breast cancer results remain controversial. We set out to clarify the role of YAP1 in breast cancer by examining gene and protein expression in subgroups of patient material and by downregulating YAP1 in vitro and studying its role in response to the widely used anti-estrogen tamoxifen. Methods: YAP1 protein intensity was scored as absent, weak, intermediate or strong in two primary breast cancer cohorts (n = 144 and n = 564) and mRNA expression of YAP1 was evaluated in a gene expression dataset (n = 1107). Recurrence-free survival was analysed using the log-rank test and Cox multivariate analysis was used to test for independence. WST-1 assay was employed to measure cell viability and a luciferase ERE (estrogen responsive element) construct was used to study the effect of tamoxifen, following downregulation of YAP1 using siRNAs. Results: In the ER+ (Estrogen Receptor a positive) subgroup of the randomised cohort, YAP1 expression was inversely correlated to histological grade and proliferation (p = 0.001 and p = 0.016, respectively) whereas in the ER-(Estrogen Receptor a negative) subgroup YAP1 expression correlated positively to proliferation (p = 0.005). Notably, low YAP1 mRNA was independently associated with decreased recurrence-free survival in the gene expression dataset, specifically for the luminal A subgroup (p less than 0.001) which includes low proliferating tumours of lower grade, usually associated with a good prognosis. This subgroup specificity led us to hypothesize that YAP1 may be important for response to endocrine therapies, such as tamoxifen, extensively used for luminal A breast cancers. In a tamoxifen randomised patient material, absent YAP1 protein expression was associated with impaired tamoxifen response which was significant upon interaction analysis (p = 0.042). YAP1 downregulation resulted in increased progesterone receptor (PgR) expression and a delayed and weaker tamoxifen in support of the clinical data. Conclusions: Decreased YAP1 expression is an independent prognostic factor for recurrence in the less aggressive luminal A breast cancer subgroup, likely due to the decreased tamoxifen sensitivity conferred by YAP1 downregulation.

  • 77.
    Linderholm, B K.
    et al.
    Sahlgrens Acad, Sweden .
    Linder, S
    Karolinska Institute, Sweden .
    Arnesson, Lars-Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Identification of intermediate risk breast cancer patients with1-3 positive lymph nodes and excellent survival after tamoxifen as only systemic adjuvant therapy by use of markers of proliferation and apoptosis2013Ingår i: Breast, ISSN 0960-9776, E-ISSN 1532-3080, Vol. 22, nr 5, s. 643-649Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: According to current guidelines, patients with primary breast cancer and 1-3 lymph node metastases will in general be offered adjuvant chemotherapy. less thanbrgreater than less thanbrgreater thanAim: Our objective was to investigate the relationship between markers of proliferation and apoptosis with survival for patients subjected to adjuvant tamoxifen solely. less thanbrgreater than less thanbrgreater thanMaterial and methods: Tumour cytosol samples from 409 consecutive patients with operable oestrogen receptor positive BC, stage I-III and treated with tamoxifen for 2 or 5 years were assessed for levels of caspase-cleaved cytokeratin-18 (ccCK18), an indicator of apoptosis, by use of an ELISA assay. Data on S-phase fraction (SPF) were available for 370 patients. Survival analyses were performed according to levels of ccCK18 and SPF separately, as well as combined. less thanbrgreater than less thanbrgreater thanResults: A wide range of ccCK18 protein levels was found, median 9.97, range 0.0-87.3 pg/mu gDNA. Increasing SPFs were significantly associated with a lower distant recurrence-free survival (DRFS) (p = 0.025) and breast cancer survival (BCS) (p = 0.046). In the group with low SPF (below mean), low amounts of ccCK/18 correlated with a shorter DRFS (p = 0.0028) and BCS (p = 0.0027). A Proliferation Index (PI); a quotient of ccCK18/SPF was constructed. Low PI (high ccCK18/SPF ratios) were significantly correlated with an improved survival both when analysed as continuous variables; DRFS (p = 0.021), BCS (p = 0.038) and when divided into quartiles; DRFS (p andlt; 0.001) and BCS (p = 0.0012). A similar correlation was found in patients with 1-3 lymph node metastases; DRFS (p = 0.089) and BCS (p = 0.019). A Coxs proportional hazard model including age, tumour size, lymph node status, PgR and ccCK18/SPF was used for multivariate analysis. High ccCK18/SPF ratios correlated with improved survival; DRFS (HR = 0.47 (0.22-0.98), p = 0.043), and BCS (HR = 0.39 (0.16-1.00), p = 0.049), respectively. less thanbrgreater than less thanbrgreater thanConclusion: By use of a proliferation index based on markers of proliferation and apoptosis, a group of patients with 1-3 lymph node metastases with good outcome following adjuvant tamoxifen was identified; this group could possibly be spared adjuvant chemotherapy.

  • 78.
    Lundgren, Katja
    et al.
    Lund University.
    Tobin, Nicholas P
    Lund University.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Ryden, Lisa
    Lund University.
    Jirstrom, Karin
    Lund University.
    Landberg, Goran
    University of Manchester.
    Stromal Expression of beta-Arrestin-1 Predicts Clinical Outcome and Tamoxifen Response in Breast Cancer2011Ingår i: Journal of Molecular Diagnostics, ISSN 1525-1578, E-ISSN 1943-7811, Vol. 13, nr 3, s. 340-351Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The G-protein coupled receptor associated protein beta-arrestin-1 is crucial for the regulation of numerous biological processes involved in cancer progression, such as intracellular signaling and cell motility. The encoding gene ARRB1 is harbored in the same chromosomal region as the CCND1 gene (11q13). Amplification of CCND1, frequently encountered in breast cancer, often involves coamplification of additional oncogenes, as well as deletion of distal 11q genes. We investigated the clinical relevance of beta-arrestin-1 in breast cancer and elucidated a potential link between beta-arrestin-1 expression and CCND1 amplification. beta-Arrestin-1 protein expression was evaluated in two breast cancer patient cohorts, comprising 179 patients (cohort I) and 500 patients randomized to either tamoxifen or no adjuvant treatment (cohort H). Additionally, migration after beta-arrestin-1 overexpression or silencing was monitored in two breast cancer cell lines. Overexpression of beta-arrestin-1 reduced the migratory propensity of both cell lines, whereas silencing increased migration. In cohort I, high expression of stromal beta-arrestin-1 was linked to reduced patient survival, whereas in cohort II both high and absent stromal expression predicted a poor clinical outcome. Patients exhibiting low or moderate levels of stromal beta-arrestin-1 did not benefit from tamoxifen, in contrast to patients exhibiting absent or high expression. Furthermore, CCND1 amplification was inversely correlated with tumor cell expression of beta-arrestin-1, indicating ARRB1 gene deletion in CCND1-amplified breast cancers.

  • 79.
    Manna, Subrata
    et al.
    Department of Biology; Stern College for Women of Yeshiva University; New York, New York, USA.
    Bostner, Josefine
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Sun, Yang
    Division of Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
    Miller, Lance D
    Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina. The Comprehensive Cancer Center of Wake Forest University, Winston Salem, North Carolina, USA.
    Alayev, Anya
    Department of Biology; Stern College for Women of Yeshiva University; New York, New York, USA.
    Schwartz, Naomi S
    Department of Biology; Stern College for Women of Yeshiva University; New York, New York, USA.
    Lager, Elin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Fornander, Tommy
    Department of Oncology, Karolinska University Hospital, Stockholm South General Hospital, Karolinska Institute, Stockholm, Sweden.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Yu, Jane J
    Division of Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Holz, Marina K
    Department of Biology; Stern College for Women of Yeshiva University; New York, New York. Department of Molecular Pharmacology, Albert Einstein College of Medicine, New York, New York, USA.
    ERRα Is a Marker of Tamoxifen Response and Survival in Triple-Negative Breast Cancer.2016Ingår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 22, nr 6, s. 1421-1431Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PURPOSE: Estrogen-related receptor alpha (ERRα) signaling has recently been implicated in breast cancer. We investigated the clinical value of ERRα in randomized cohorts of tamoxifen-treated and adjuvant-untreated patients.

    EXPERIMENTAL DESIGN: Cox proportional hazards regression was used to evaluate the significance of associations between ERRα gene expression levels and patient DMFS in a previously published microarray dataset representing 2,000 breast tumor cases derived from multiple medical centers worldwide. The 912 tumors used for immunostaining were from a tamoxifen-randomized primary breast cancer trial conducted in Stockholm, Sweden, during 1976-1990. Mouse model was used to study the effect of tamoxifen treatment on lung colonization of MDA-MB-231 control cells and MDA-MB-231 cells with stable knockdown of ERRα. The phenotypic effects associated with ERRα modulation were studied using immunoblotting analyses and wound-healing assay.

    RESULTS: We found that in ER-negative and triple-negative breast cancer (TNBC) adjuvant-untreated patients, ERRα expression indicated worse prognosis and correlated with poor outcome predictors. However, in tamoxifen-treated patients, an improved outcome was observed with high ERRα gene and protein expression. Reduced ERRα expression was oncogenic in the presence of tamoxifen, measured by in vitro proliferation and migration assays and in vivo metastasis studies.

    CONCLUSION: Taken together, these data show that ERRα expression predicts response to tamoxifen treatment, and ERRα could be a biomarker of tamoxifen sensitivity and a prognostic factor in TNBC. Clin Cancer Res; 1-11. ©2015 AACR.

  • 80.
    Miller, T W
    et al.
    Vanderbilt University.
    Perez-Torres, M
    Vanderbilt University.
    Wu, H
    Vanderbilt University.
    Shyr, Y
    Vanderbilt University.
    Guix, M
    Vanderbilt University.
    Jiang, A
    Vanderbilt University.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Arteaga, C L
    Vanderbilt University.
    Loss of PTEN engages ErbB3 and IGF-I receptor signaling to promote antiestrogen resistance in breast cancer.2009Ingår i: CANCER RESEARCH ISSN 0008-5472: Volume 69 Issue 2, 2009, Vol. 69, nr 2, s. 80S-81SKonferensbidrag (Refereegranskat)
  • 81.
    Niméus-Malmström, Emma
    et al.
    Institute of Clinical Sciences, Department of Oncology, University Hospital, Lund, Sweden.
    Krogh, Morten
    Computational Biology and Biological Physics, Department of Theoretical Physics, Lund University, Lund, Sweden .
    Malmström, Per
    Institute of Clinical Sciences, Department of Oncology, University Hospital, Lund, Sweden.
    Strand, Carina
    Institute of Clinical Sciences, Department of Oncology, University Hospital, Lund, Sweden.
    Fredriksson, Irma
    Department of Surgery, Karolinska University Hospital in Solna, Stockholm, Sweden .
    Karlsson, Per
    Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden .
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Östberg, Görel
    Department of Pathology, Halmstad Hospital, Halmstad, Sweden .
    Peterson, Carsten
    Computational Biology and Biological Physics, Department of Theoretical Physics, Lund University, Lund, Sweden .
    Ferno, Marten
    Institute of Clinical Sciences, Department of Oncology, University Hospital, Lund, Sweden.
    Gene expression profiling in primary breast cancer distinguishes patients developing local recurrence after breast-conservation surgery, with or without postoperative radiotherapy2008Ingår i: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 10, nr 2Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction

    Some patients with breast cancer develop local recurrence after breast-conservation surgery despite postoperative radiotherapy, whereas others remain free of local recurrence even in the absence of radiotherapy. As clinical parameters are insufficient for identifying these two groups of patients, we investigated whether gene expression profiling would add further information.

    Methods

    We performed gene expression analysis (oligonucleotide arrays, 26,824 reporters) on 143 patients with lymph node-negative disease and tumor-free margins. A support vector machine was employed to build classifiers using leave-one-out cross-validation.

    Results

    Within the estrogen receptor-positive (ER+) subgroup, the gene expression profile clearly distinguished patients with local recurrence after radiotherapy (n = 20) from those without local recurrence (n = 80 with or without radiotherapy). The receiver operating characteristic (ROC) area was 0.91, and 5,237 of 26,824 reporters had a P value of less than 0.001 (false discovery rate = 0.005). This gene expression profile provides substantially added value to conventional clinical markers (for example, age, histological grade, and tumor size) in predicting local recurrence despite radiotherapy. Within the ER- subgroup, a weaker, but still significant, signal was found (ROC area = 0.74). The ROC area for distinguishing patients who develop local recurrence from those who remain local recurrence-free in the absence of radiotherapy was 0.66 (combined ER+/ER-).

    Conclusion

    A highly distinct gene expression profile for patients developing local recurrence after breast-conservation surgery despite radiotherapy has been identified. If verified in further studies, this profile might be a most important tool in the decision making for surgery and adjuvant therapy.

  • 82.
    Perez-Tenorio, Gizeh
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Berglund, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Esguerra Merca, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Rutqvist, Lars Erik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Skoog, Lambert
    Institutionen för cytology, Karolinska Hospital, Stockholm, Sweden.
    Stål , Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Cytoplasmic p21WAF1/CIP1 correlates with Akt activation and poor response to tamoxifen in breast cancer2006Ingår i: International Journal of Oncology, ISSN 1019-6439, Vol. 28, nr 5, s. 1031-1042Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    P21WAF1/Cip1 (p21) translocates to the cytoplasm inducing cell cycle progression and survival upon Akt/PKB activation. We studied whether heregulin beta1 (HRGbeta1), that activates the PI3K/Akt and MAPK pathways, also misallocates p21. We also explored whether HRGbeta1 interferes with the effects of tamoxifen. The clinical material studied helped us to clarify whether p21 was associated with phosphorylated Akt, recurrence-free survival and response to tamoxifen. MCF-7 cells treated with HRGbeta1 -/+ E2 were analyzed by flow cytometry to observe how the different compounds affected tamoxifen-induced cell cycle arrest and apoptosis. Total cell lysate and nuclear and cytoplasmic fractions were used to detect p21, phospho-Akt and other proteins by Western blotting. Immunofluorescence was used to visualize p21+ cells upon HRGbeta1 and E2 stimulation. The localization of p21 in breast cancer was studied by immunohistochemistry in frozen tumor sections from 280 patients. In MCF-7 we found that HRGbeta1 counteracted the inhibition of p21 expression by tamoxifen and caused p21 cytoplasmic accumulation. HRGbeta1 partially counteracted the cytostatic effect of tamoxifen but abrogated its cytotoxic effect. The clinical material revealed that nuclear p21 (P=0.022) and cytoplasmic p21 (P=0.00001) were associated with phospho-Akt. Based on p21 cell location, we identified 3 subgroups of ER+ patients: the p21N+/C- group for whom tamoxifen was needed otherwise the survival was poor (P=0.0082), the p21N+/C+ or p21N-/C- group, that responded to tamoxifen (P=0.034), and the p21C+/N- group, that might not benefit from this treatment (P=0.7). In conclusion, HRGbeta1 inhibits tamoxifen-induced apoptosis, contributes to p21 cytoplasmic expression while the cellular localization of p21 interacts with the benefit from tamoxifen treatment.

  • 83.
    Perez-Tenorio, Gizeh
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Karlsson, Elin
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi.
    Ahnström, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Olsson, Birgit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Holmlund, Birgitta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Fornander, Tommy
    Karolinska University Hospital, Department Oncol, S-11883 Stockholm, Sweden.
    Skoog, Lambert
    Karolinska University Hospital, Department Pathol and Cytol, S-17176 Stockholm, Sweden.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer2011Ingår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 128, nr 3, s. 713-723Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The mammalian target of rapamycin (mTOR) and its substrates S6K1 and S6K2 regulate cell growth, proliferation, and metabolism through translational control. RPS6KB1 (S6K1) and RPS6KB2 (S6K2) are situated in the commonly amplified 17q21-23 and 11q13 regions. S6K1 amplification and protein overexpression have earlier been associated with a worse outcome in breast cancer, but information regarding S6K2 is scarce. The aim of this study was to evaluate the prognostic and treatment predictive relevance of S6K1/S6K2 gene amplification, as well as S6K2 protein expression in breast cancer. S6K1/S6K2 gene copy number was determined by real-time PCR in 207 stage II breast tumors and S6K2 protein expression was investigated by immunohistochemistry in 792 node-negative breast cancers. S6K1 amplification/gain was detected in 10.7%/21.4% and S6K2 amplification/gain in 4.3%/21.3% of the tumors. S6K2 protein was detected in the nucleus (38%) and cytoplasm (76%) of the tumor cells. S6K1 amplification was significantly associated with HER2 gene amplification and protein expression. S6K2 amplification correlated significantly with high S6K2 mRNA levels, ER+ status and CCND1 amplification. S6K1 and S6K2 gene amplification was associated with a worse prognosis independent of HER2 and CCND1. S6K2 gain and nuclear S6K2 expression was related to an improved benefit from tamoxifen among patients with ER+, respectively ER+/PgR+ tumors. In the ER+/PgR- subgroup, nuclear S6K2 rather indicated decreased tamoxifen responsiveness. S6K1 amplification predicted reduced benefit from radiotherapy. This is the first study showing that S6K2 amplification and overexpression, like S6K1 amplification, have prognostic and treatment predictive significance in breast cancer.

  • 84.
    Perez-Tenorio, Gizeh
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Karlsson, Elin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Ahnström Waltersson, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Olsson, Birgit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Holmlund, Birgitta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Fornander, Tommy
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Skoog, Lambert
    Department of Cytology, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Clinical Value of RPS6KB1 and RPS6KB2 Gene Amplification in Postmenopausal Breast Cancer2008Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The mammalian target of rapamycin (mTOR) and its substrates the ribosomal S6 kinases (S6K)1 and 2 integrate nutrient and hormonal/growth factor mediated signals and are implicated indiabetes, obesity and cancer. The genes encoding S6K1 (RPS6KB1) and S6K2 (RPS6KB2) aresituated close to well known amplicons but information regarding its expression and clinicalvalue is scarce. In this study we quantified RPS6KB1/2 gene copy number, establishedassociations with other clinical factors and explored their clinical value in breast cancer. RPS6KB1/2 copy number was determined by fast real-time PCR in 207 breast tumors.RPS6KB1 was amplified (≥ 4 copies) in 10.7% (22/206) and RPS6KB2 in 4.3% (9/207) of thetumors. Amplification of RPS6KB1 was associated with HER2 gene amplification (P=0.025)and protein expression (P=0.014) while RPS6KB2 correlated with ER+ status (P=0.046) and CCND1 amplification (P<0.00001). In a multivariate analysis, both genes were independentprognostic factors indicating higher risk to develop recurrences. In terms of loco regionalcontrol, amplification of the RPS6KB1 gene predicted less response to radiotherapy (P=0.035) while RPS6KB2 gene copy gain (≥ 3 copies) indicated increased benefit from tamoxifen (P=0.03) among ER+ patients. S6K1/2 gene amplification could be used as an indicator oftherapy response among postmenopausal breast cancer patients.

  • 85.
    Pérez-Tenorio, Gizeh
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Alkhori, Liza
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Olsson, Birgit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Ahnstro Waltersson, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Rutqvist, Lars Erik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Skoog, Lambert
    Institutionen för Cytology, Karolinska Hospital, Stockholm, Sweden.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer2007Ingår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 13, nr 12, s. 3577-3584Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose: The phosphatidylinositol 3'-kinase/Akt pathway is frequently altered in breast cancer. PTEN, a phosphatase that opposes the effect of phosphatidylinositol 3'-kinase, can be mutated or lost, whereas the PIK3CA gene is mutated. These have been proposed as alternative mechanisms, and their clinicalpathology significance is under discussion. In this study, we aimed to explore whether PIK3CA mutations and PTEN loss are mutually exclusive mechanisms, correlate with other known clinicopathologic markers, or have clinical implication in breast cancer.

    Experimental Design: Exons 9 and 20 of the PIK3CA gene were analyzed in 270 breast tumors, and mutations were detected by single-stranded conformational analysis followed by sequencing. The expression of PTEN was evaluated by immunohistochemistry in 201 tumors.

    Results: PIK3CA mutations were found in 24% of the tumors and associated with estrogen receptor(+) status, small size, negative HER2 status, high Akt1, and high cyclin D1 protein expression. PTEN was negative in 37% of the cases and PTEN loss was associated with PIK3CA mutations (P = 0.0024). Tumors presenting PTEN loss or both alterations were often estrogen receptor(+), small in size, and HER2(-). PIK3CA mutations predicted for longer local recurrence-free survival. Moreover, PTEN loss by itself or combined with mutated PIK3CA tended to confer radiosensitivity. In addition, the patients with high S-phase fraction had longer recurrence-free survival if they carried mutations in the PIK3CA gene and/or had lost PTEN, whereas the same alterations were associated with shorter recurrence-free survival among patients with low S-phase fraction.

    Conclusions: PIK3CA mutations and PTEN loss were not mutually exclusive events and associated with similar prognostic factors.

  • 86.
    Pérez-Tenorio, Gizeh
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Members of the Southeast Sweden Breast Cancer Group,
    Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients2002Ingår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 86, nr 4, s. 540-545Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Akt/PKB is a serine/threonine protein kinase that regulates cell cycle progression, apoptosis and growth factor mediated cell survival in association with tyrosine kinase receptors. The protein is a downstream effector of erbB-2 with implications in breast cancer progression and drug resistance in vitro. We aimed to examine the role of Akt-1 in breast cancer patients, by determining whether the expression (Akt-1) and/or activation (pAkt) were related to prognostic markers and survival. The expression of erbB-2, heregulin β1 and Bcl-2 was also assessed by flow cytometry or immunohistochemistry. This study comprised 93 patients, aged < 50 who were treated with tamoxifen and/or goserelin. We found that pAkt was associated with lower S-phase fraction (P = 0.001) and the presence of heregulin β1-expressing stromal cells (P = 0.017). Neither Akt-1 nor pAkt was related with other factors Turnout cells-derived heregulin β1 was found mainly in oestrogen receptor negative (P = 0.026) and node negative (P = 0.005) cases. Survival analysis revealed that pAkt positive patients were more prone to relapse with distant metastasis, independently of S-phase fraction and nodal status (multivariate analysis; P = 0.004). The results suggest that activation of Akt may have prognostic relevance in breast cancer

  • 87.
    Razavi, Amir Reza
    et al.
    Linköpings universitet, Institutionen för medicinsk teknik, Medicinsk informatiK. Linköpings universitet, Tekniska högskolan.
    Gill, Hans
    Linköpings universitet, Institutionen för medicinsk teknik, Medicinsk informatiK. Linköpings universitet, Tekniska högskolan.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Sundquist, Marie
    Department of Surgery, County Hospital, Kalmar, Sweden.
    Thorstenson, Sten
    Department of Pathology, County Hospital, Kalmar, Sweden.
    Åhlfeldt, Hans
    Linköpings universitet, Institutionen för medicinsk teknik, Medicinsk informatiK. Linköpings universitet, Tekniska högskolan.
    Shahsavar, Nosrat
    Linköpings universitet, Institutionen för medicinsk teknik, Medicinsk informatiK. Linköpings universitet, Tekniska högskolan.
    The South-East Swedish Breast Cancer Study Group,
    Exploring cancer register data to find risk factors for recurrence of breast cancer: Application of Canonical Correlation Analysis2005Ingår i: BMC Medical Informatics and Decision Making, ISSN 1472-6947, Vol. 5, nr 29, s. 29-35Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    A common approach in exploring register data is to find relationships between outcomes and predictors by using multiple regression analysis (MRA). If there is more than one outcome variable, the analysis must then be repeated, and the results combined in some arbitrary fashion. In contrast, Canonical Correlation Analysis (CCA) has the ability to analyze multiple outcomes at the same time.

    One essential outcome after breast cancer treatment is recurrence of the disease. It is important to understand the relationship between different predictors and recurrence, including the time interval until recurrence. This study describes the application of CCA to find important predictors for two different outcomes for breast cancer patients, loco-regional recurrence and occurrence of distant metastasis and to decrease the number of variables in the sets of predictors and outcomes without decreasing the predictive strength of the model.

    Methods

    Data for 637 malignant breast cancer patients admitted in the south-east region of Sweden were analyzed. By using CCA and looking at the structure coefficients (loadings), relationships between tumor specifications and the two outcomes during different time intervals were analyzed and a correlation model was built.

    Results

    The analysis successfully detected known predictors for breast cancer recurrence during the first two years and distant metastasis 2–4 years after diagnosis. Nottingham Histologic Grading (NHG) was the most important predictor, while age of the patient at the time of diagnosis was not an important predictor.

    Conclusion

    In cancer registers with high dimensionality, CCA can be used for identifying the importance of risk factors for breast cancer recurrence. This technique can result in a model ready for further processing by data mining methods through reducing the number of variables to important ones.

  • 88.
    Rosell, Johan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för hälso- och vårdutveckling, Regionalt cancercentrum.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Bengtsson, Nils-Olof
    Umeå University Hospital, Sweden .
    Fornander, Tommy
    Karolinska University Hospital, Sweden .
    Hatschek, Thomas
    Karolinska University Hospital, Sweden .
    Lindman, Henrik
    University of Uppsala Hospital, Sweden .
    Malmstrom, Per-Olof
    Skåne University Hospital, Sweden .
    Wallgren, Arne
    Sahlgrens University Hospital, Sweden .
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Carstensen, John
    Linköpings universitet, Institutionen för medicin och hälsa, Hälsa och samhälle. Linköpings universitet, Hälsouniversitetet.
    Effects of adjuvant tamoxifen therapy on cardiac disease: results from a randomized trial with long-term follow-up2013Ingår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 138, nr 2, s. 467-473Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Tamoxifen is associated with a reduced risk of coronary heart disease (CHD). However, there are few reports on long-term effects. Using data from a large Swedish randomized trial of 5 and 2 years of adjuvant tamoxifen in women with early breast cancer, we here present results on morbidity and mortality from cardiac diseases during treatment and long-term after treatment. A total of 4,150 patients were breast cancer recurrence-free after 2 years. Data from the Swedish National Hospital Discharge Registry combined with information from the Swedish Cause of Death Registry were used to define events of disease. Hazard ratios were estimated using Cox regression. Patients assigned to 5 years in comparison with 2 years of postoperative tamoxifen experienced a reduced incidence of CHD [hazard ratio (HR), 0.83; 95 % CI 0.70-1.00], especially apparent during the active treatment period (HR 0.65; 95 % CI 0.43-1.00). The mortality from CHD was significantly reduced (HR 0.72; 95 % CI 0.53-0.97). During the active treatment, the morbidity of other heart diseases was also significantly reduced (HR 0.40; 95 % CI 0.25-0.64) but not after treatment stopped (HR 1.06; 95 % CI 0.87-1.30). Similar results were seen for both heart failure and atrial fibrillation/flutter. As compared to 2 years of therapy, 5 years of postoperative tamoxifen therapy prevents CHD as well as other heart diseases. The risk reduction is most apparent during the active treatment period, and later tends to diminish.

  • 89.
    Rosell, Johan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för hälso- och vårdutveckling, Regionalt cancercentrum.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Bengtsson, Nils-Olof
    Umeå University Hospital, Sweden .
    Fornander, Tommy
    Karolinska University Hospital, Sweden .
    Hatschek, Thomas
    Karolinska University Hospital, Sweden .
    Lindman, Henrik
    University of Uppsala Hospital, Sweden .
    Malmstrom, Per-Olof
    Skåne University Hospital, Sweden .
    Wallgren, Arne
    Sahlgrens University Hospital, Sweden .
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Carstensen, John
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för hälso- och sjukvårdsanalys. Linköpings universitet, Hälsouniversitetet.
    Effects of adjuvant tamoxifen therapy on the incidence of secondary cancer: results from a randomized trial with long term follow-up2014Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    BACKGROUND

    Tamoxifen is a well-established endocrine treatment for breast cancer. We here present results with respect to second primary cancer from a large randomized trial of 5 and 2 years of adjuvant tamoxifen. Breast cancer distant recurrence and mortality are also reported.

    METHODS

    Our study included 4128 postmenopausal patients with early stage breast cancer who were alive and free of breast cancer recurrence after 2 years of tamoxifen therapy. They were randomized to receive three more years of therapy or stop tamoxifen. In the comparison of 5 years versus 2 years of postoperative tamoxifen treatment hazard ratios were estimated using Cox regression for different follow-up periods defined as: During treatment (2-5 years) and after treatment (5-10 years, 10-15 years, > 5 years, > 10 years and > 15 years).

    RESULTS

    In the five years group the incidence of lung cancer was halved (hazard ratio [HR], 0.45, 95% confidence interval [95% CI], 0.27-0.77 [P = .0038]), and lung cancer mortality was decreased. An increased risk was observed for endometrial cancer (HR, 1.83; 95% CI, 1.19-2.81 [P = .0059]), but this risk appeared to decrease over time. The risk of contralateral breast cancer was decreased (HR, 0.73; 95% CI, 0.56-0.96 [P = .022]), also in the period after treatment stopped. In the five years group, the risk of distant recurrence was decreased, and statistically significant reductions were observed both during treatment and in the five year period after treatment stopped. The breast cancer mortality was reduced, especially during the post-treatment phase.

    CONCLUSIONS

    In this randomized study, tamoxifen substantially reduces the risk of new cancer both in contralateral breast and in lung up to 10 years after treatment stopped.

  • 90.
    Rosell, Johan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Bengtsson, N-O
    Department of Oncolog, Umea University Hospital, Sweden.
    Fornander, T
    Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Hatschek, T
    Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Lindman, H
    Department of Oncology, Uppsala University Hospital, Uppsala, Sweden.
    Malmstrom, P-O
    Department of Oncology, Lund University Hospital, Lund, Sweden.
    Wallgren, A
    Department of Oncology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Carstensen, John
    Linköpings universitet, Institutionen för medicin och hälsa, Hälsa och samhälle. Linköpings universitet, Hälsouniversitetet.
    Time dependent effects of adjuvant tamoxifen therapy on cerebrovascular disease: results from a randomised trial2011Ingår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 104, nr 6, s. 899-902Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Tamoxifen has been associated with an increased risk of stroke. There is, however, little information on the effect in the post-treatment period. Using data from the Swedish Breast Cancer Group adjuvant trial of 5 vs 2 years of tamoxifen treatment, we now report both short-term and long-term effects on morbidity as well as mortality because of cerebrovascular disease. METHODS: Data from the Swedish National Hospital Discharge Registry combined with information from the Swedish Cause of Death Registry was used to define events of disease. Hazard ratios (HRs) were estimated using Cox regression. RESULTS: Comparing patients randomised to 5 years of tamoxifen with patients randomised to 2 years of tamoxifen, the incidence of cerebrovascular diseases was increased (HR 1.70, 95% CI 1.05-2.75) during the active treatment phase and reduced after the active treatment period (HR 0.78, 95% CI 0.63-0.96), and the difference in HR between the two time-periods was significant (P 0.0033). The mortality from cerebrovascular diseases was increased during the treatment period (HR 3.18, 95% CI 1.03-9.87) and decreased during the post-treatment period (HR 0.60, 95% CI 0.40-0.90) with a significant difference in HR between the two periods of follow-up (P=0.0066). Similar results were seen for subgroups of cerebrovascular diseases, such as stroke and ischaemic stroke. CONCLUSION: In an adjuvant setting, tamoxifen was associated with an increased risk of cerebrovascular disease during treatment, but a decreased risk in the post-treatment period.

  • 91. Ryden, L
    et al.
    Jirstrom, K
    Bendahl, PA
    Ferno, M
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Thorstenson, Sten
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Jonsson, PE
    Landberg, G
    Tumor-specific expression of vascular endothelial growth factor receptor 2 but not vascular endothelial growth factor or human epidermal growth factor receptor 2 is associated with impaired response to adjuvant tamoxifen in premenopausal breast cancer2005Ingår i: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 23, nr 21, s. 4695-4704Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose Vascular endothelial growth factor A (VEGF-A) and vascular endothelial growth factor receptor 2 (VEGFR2) are often coexpressed in breast cancer, and potentially affect cellular pathways and key proteins such as the estrogen receptor (ER) targeted by endocrine treatment. We therefore explored the association between adjuvant tamoxifen treatment in breast cancer and expression of VEGF-A and VEGFR2, as well as human epidermal growth factor receptor 2 (HER2), which represents a candidate gene product involved in tamoxifen resistance.

    Patients and Methods Immunohistochemical expression of tumor-specific VEGF-A, VEGFR2, and HER2 was evaluated in tumor specimens from premenopausal breast cancer patients randomly assigned to 2 years of tamoxifen or no treatment (n = 564), with 14 years of follow-up. Hormone receptor status was determined in 96% of the tumors.

    Results VEGF-A, VEGFR2, and HER2 were assessable in 460, 472, and 428 of the tumors, respectively. In patients with ER–positive and VEGFR2-low tumors, adjuvant tamoxifen significantly increased recurrence-free survival (RFS; [HR] hazard ratio for RFS, 0.53; P = .001). In contrast, tamoxifen treatment had no effect in patients with VEGFR2-high tumors (HR for RFS, 2.44; P = .2). When multivariate interaction analyses were used, this difference in treatment efficacy relative to VEGFR2 expression status was statistically significant for both ER-positive (P = .04) plus ER-positive and progesterone receptor–positive tumors. We found no significant difference in tamoxifen treatment effects in relation to VEGF-A or HER2 status.

    Conclusion Tumor-specific expression of VEGFR2 was associated with an impaired tamoxifen effect in hormone receptor–positive premenopausal breast cancer. Tamoxifen in combination with VEGFR2 inhibitors might be a novel treatment approach for VEGFR2-expressing breast cancer, and such a treatment might restore the tamoxifen response.

  • 92.
    Ryden, Lisa
    et al.
    Lund University Hospital.
    Jirstrom, Karin
    Lund University.
    Haglund, Monica
    Lund University.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Ferno, Marten
    Lund University.
    Epidermal growth factor receptor and vascular endothelial growth factor receptor 2 are specific biomarkers in triple-negative breast cancer. Results from a controlled randomized trial with long-term follow-up2010Ingår i: BREAST CANCER RESEARCH AND TREATMENT, ISSN 0167-6806, Vol. 120, nr 2, s. 491-498Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Triple-negative breast cancer (TNB) has poor prognosis and moreover patients with TNB do not benefit from established targeted drugs with endocrine therapy or trastuzumab. The aim of the study was to analyze the prevalence of candidate biomarkers in tumors from patients with TNB. Tissue microarrays were prepared from primary tumors from premenopausal breast cancer patients (500/564) randomized to adjuvant tamoxifen or no adjuvant treatment. Immunohistochemical (IHC) staining included ER, PR, HER2, epidermal receptor growth factor (EGFR), vascular endothelial growth factor A (VEGF-A), and vascular endothelial growth factor receptor 2 (VEGFR2). EGFR and HER2 gene copy number was defined by fluorescence in situ hybridization (FISH). All patients were included in the descriptive analysis, but only untreated patients in the survival analysis. TNB was diagnosed in 96 patients and correlated significantly to low age, Nottingham histological grade (NHG) III, high Ki67-index, T2 tumors, node negativity, EGFR positivity, increased EGFR gene copy number and high VEGFR2 expression. TNB was an independent prognostic factor for decreased 5-year breast cancer specific survival (BCSS) (HR 2.0 (95% CI 1.1-3.6), P = 0.01), but not for 10-year BCSS. High VEGFR2 expression was significantly correlated to decreased BCSS in TNB patients. TNB was associated with decreased BCSS and clinicopathological characteristics of an aggressive tumor type. High VEGFR2 expression, EGFR expression, and EGFR gene copy number were significantly correlated to TNB, supporting their role as putative candidate biomarkers for selection of targeted therapy in TNB.

  • 93.
    Rydén, Lisa
    et al.
    Department of Surgery, Helsingborgs Lasarett, Helsingborg, Sweden and Department of Laboratory Medicine, div of Pathology, University Hospital, Malmö.
    Jönsson, Per-Ebbe
    Department of Surgery, Helsingborgs Lasarett, Helsingborg, Sweden.
    Chebil, Gunilla
    Department of Pathology, Helsingborgs Lasarett, Helsingborg.
    Dufmats, Monika
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Fernö, Mårten
    Department of Oncology, University Hospital, Lund.
    Jirström, Karin
    Department of Laboratory Medicine, div of Pathology, University Hospital, Malmö.
    Källström, Ann-Christine
    Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala.
    Landberg, Göran
    Department of Laboratory Medicine, div of Pathology, University Hospital, Malmö.
    Stål, Olle
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Thorstenson, Sten
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Two years of adjuvant tamoxifen in premenopausal patients with breast cancer: a randomised, controlled trial with long-term follow-up2005Ingår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 41, nr 2, s. 256-264Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Adjuvant tamoxifen treatment increases recurrence-free survival (RFS) and overall survival (OS) in early breast cancer, although in premenopausal patients the number of studies comparing tamoxifen vs no treatment are limited. We report herein the effect on RFS of adjuvant tamoxifen treatment in a multicentre trial of premenopausal patients with stage II breast cancer patients randomised between 1986 and 1991 to 2 years of tamoxifen treatment (n = 276) or no treatment (n = 288). The receptor status of the tumour was known for 541 (96%) of the patients included. Tamoxifen treatment significantly increased RFS in patients with hormone receptor-positive (oestrogen receptor-positive (ER+) and/or progesterone receptor-positive (PR+)) tumours (Relative Risk (RR) 0.65; 95% Confidence Interval (CI): 0.48–0.89, P = 0.006), and the beneficial effect of tamoxifen was extended to patients with indicators of poor prognosis, such as young age and nodal-positivity. PR status was a significant predictor of response to tamoxifen in multivariate models with testing of interactions of hormone receptor status and adjuvant therapy.

  • 94.
    Rydén, Lisa
    et al.
    Department of Surgery, Institution of Clinical Sciences, Lund University, Sweden.
    Landberg, Göran
    Division of Pathology, Institution of Laboratory Medicine, Malmö University Hospital, Sweden.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Fernö, Mårten
    Department of Oncology, Institition of Clinical Sciences, Lund University, Lund, Sweden.
    Bendahl, Pär-Ola
    Department of Oncology, Institition of Clinical Sciences, Lund University, Lund, Sweden.
    HER2 status in hormone receptor positive premenopausal primary breast cancer adds prognostic, but not tamoxifen treatment predictive, information2008Ingår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 109, nr 2, s. 351-357Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    Overexpression of human epidermal growth factor receptor 2 (HER2) or amplification of its gene is a prognostic factor in primary breast cancer and a predictor for tamoxifen treatment efficacy in oestrogen receptor (ER) positive disease. In the present study we explored a defined cohort of breast cancer patients included in a randomised trial in order to assess prognostic and tamoxifen treatment information yielded by HER2 status.

    Methods

    Premenopausal breast cancer patients with stage II tumours (n = 564) were included and allocated to 2 years of adjuvant tamoxifen treatment versus no adjuvant treatment. ER, progesterone receptor (PR) status and HER2 status was determined by immunohistochemistry using a tissue microarray. HER2 amplification was analysed by fluorescent in situ hybridisation and tumours being amplified and/or HER2 3+ were considered HER2+. HER2 status was evaluable in 83% of the patients and 12.6% were HER2+. In untreated patients, HER2 was a negative prognostic factor in ER+ patients, HR 2.95; 95% CI: 1.61–5.38, p < 0.001, but not in ER- patients, HR 0.67; 95% CI: 0.28–1.61, p = 0.4, and a significant interaction between the two markers was found, p < 0.01. HER2 status was not related to tamoxifen treatment efficacy in ER+ patients (term of interaction p = 0.95). When stratifying for PR status, similar results were achieved.

    Discussion

    HER2+ and ER+ breast cancer constituted a subgroup of tumours with poor prognosis in premenopausal breast cancer, whereas no treatment interaction was found between HER2 status and tamoxifen in ER+ tumours. The poor prognosis in HER2+ and ER+ patients may interfere with the interpretation of HER2 data in non-randomised trials of adjuvant tamoxifen.

  • 95.
    Sanchez, B. C.
    et al.
    Karolinska Institute.
    Sundqvist, M.
    Kalmar Hospital.
    Fohlin, Helena
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Spyratos, F.
    Ctr Rene Huguenin, Lab Oncogenet, St Cloud, France.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Linderholm, B. K,
    Karolinska Institute.
    Prolonged tamoxifen treatment increases relapse-free survival for patients with primary breast cancer expressing high levels of VEGF2010Ingår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 46, nr 9, s. 1580-1587Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Previous retrospective studies have shown that high intratumoural levels of vascular endothelial growth factor (VEGF) correlate with an inferior outcome for patients treated with adjuvant tamoxifen. Our objectives were to validate the impact of VEGF on survival after adjuvant tamoxifen and to investigate the interaction between VEGF and treatment duration. For this purpose tumour homogenates from 402 patients with operable oestrogen receptor positive breast cancer (BC), treated with tamoxifen for 2 (n = 149) or 5 years (n = 253) as the only systemic adjuvant therapy were included. The median follow-up time for surviving patients was 9.8 years (range 0.5-14.8 years). Expression of VEGF was assessed by an enzyme-linked immunosorbent assay and investigated in relation to the standard BC parameters and survival. In the total population, higher VEGF was significantly correlated with shorter recurrence-free survival (RFS) (HR = 1.63, 95%CI = 1.11-2.39, p = 0.010), breast cancer corrected survival (BCCS) (HR = 1.82, 95%CI = 1.13-2.93, p = 0.014) and overall survival (OS) (HR = 1.51, 95%CI = 1.11-2.05, p = 0.009). High VEGF was significantly associated with reduced RFS (HR = 2.61, 95%CI = 1.45-4.70, p = 0.001) after two years of tamoxifen, whilst no difference was seen in patients treated for five years (HR = 1.09, 95%CI = 0.64-1.84, p = 0.760). A statistically significant interaction was observed between high VEGF expression and improved RFS after 5-year tamoxifen (p = 0.034). In concordance with previous studies, high VEGF was significantly correlated with shorter survival. We present data not reported previously revealing that patients expressing high levels of VEGF display a better outcome provided that tamoxifen is given for five years. Further studies on the impact of VEGF on a 5-year regimen are motivated.

  • 96.
    Shabo, Ivan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Olsson, Hans
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologisk patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Svanvik, Joar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Breast Cancer Expression of DAP12 is Associated With Skeletal and Liver Metastases and Poor Survival2013Ingår i: Clinical Breast Cancer, ISSN 1526-8209, E-ISSN 1938-0666, Vol. 13, nr 5, s. 371-377Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Macrophages are an important cellular factor in breast cancer (BRC) progression and metastasis. DNAX activating protein of 12 kD (DAP12) is essential factor for macrophage fusion function. This study was conducted to investigate the expression and significance of DAP12 expression in BRC. DAP12 is expressed in BRC cells and associated with poor survival, liver metastases, and bone metastases. These data provide new insight into the pathophysiology of macrophages in BRC. less thanbrgreater than less thanbrgreater thanBackground: The transmembrane adapter protein, DAP12, transduces activation signals for several arrays of receptors, including human signal-regulatory protein, DAP12-associating lectin-1, triggering receptor expressed on myeloid cells-1, -2, and -3, in natural killer cells, granulocytes, monocytes/macrophages, and dendritic cells. The macrophage-specific antigen, Cluster of Differentiation 163 (CD163), is expressed in breast and colorectal cancers and is associated with early cancer recurrence and poor prognosis. It was recently shown that fusion between intestinal tumor cells and macrophages results in nuclear reprogramming with hybrid transcripts from both cells of origin. The role of DAP12 in the fusion process is not known. This study investigates the expression of DAP12 in BRC cells, and its relation to other macrophage traits and to the clinical progression of disease. Materials and Methods: Immunostaining of DAP12 and CD163 was performed and evaluated in paraffin-embedded specimens from 132 patients with BRC. The outcomes were analyzed in relation to clinicopathological data. Results: DAP12 expression in cancer cells was positive in 66 percent of the cancers and was associated with high tumor grade (P = .015), and with liver (P = .047) and skeletal (P = .067), but not with lung metastases (P = 1.00). Patients with BRC expressing DAP12 had poor prognosis, with higher recurrence rates of skeletal (P = .018) and liver metastases (P = .047), and shorter survival time (P = .0060). Conclusion: We suggest that macrophage traits in BRC cells facilitate the metastatic process and that DAP12 expression might promote metastatic homing to bone and liver tissues.

  • 97.
    Shabo, Ivan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiskt centrum.
    Olsson, Hans
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologisk patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiskt centrum.
    Svanvik, Joar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiskt centrum.
    DAP12, a macrophage fusion receptor, is expressed in breast cancer cells and associated with skeletal and liver metastases and poor survivalManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    DAP12 is a transmembrane receptor present in myeloid cells and is essential for the development of functionally mature osteoclasts and microglia, and for integrin signaling in macrophages and neutrophils. The macrophage specific antigen CD163 is expressed in breast and colorectal cancer and is associated with early cancer recurrence and poor prognosis. We hypothesize that macrophage traits in cancer cells may be explained by fusion between cancer cells and tumor associated macrophages. The role of DAP12 in the fusion between cancer cells and macrophages is not known. This study was performed to investigate the expression of DAP12 in breast cancer cells and its´ relation to macrophage trait manifested by CD163 expression.

    Immunostaining of DAP12, CD163 and MAC387 were evaluated in paraffinembedded specimens from totally 133 patients with breast cancer. The outcomes were analyzed in relation to clinicopathological data.

    DAP12 expression was positive in the majority of cases (64%) with breast cancer and associated with advanced tumor grade (p= 0.015) and liver metastasis (p= 0.0465) but not lung metastasis (0.997). It tended to correlate with skeletal metastases (p=0.0673). Patients with breast cancer expressing high DAP12 had poor prognosis with higher rates of skeletal (p=0.023) and liver metastases (p=0.028) and overall shorter distant recurrence free survival (p=0.0028). DAP12 expression was neither correlated to CD163 nor MAC387 expression. To our knowledge, this is the first study where DAP12 expression is reported in breast cancer.

    In conclusion, DAP12 is expressed in breast cancer and is significantly related to skeletal and liver metastasis as well as poor prognosis. We hypothesize that DAP12 expression may promote fusion between breast cancer cells and macrophages. It may even promote homing of cancer cells in bone and liver tissue and result in increased metastasis at these sites.

  • 98.
    Shabo, Ivan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Olsson, Hans
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Linköpings universitet, Hälsouniversitetet.
    Doré, Siv
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Linköpings universitet, Hälsouniversitetet.
    Svanvik, Joar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet.
    Breast cancer expression of CD163, a macrophage scavenger receptor, is related to early distant recurrence and reduced patient survival2008Ingår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 123, nr 4, s. 780-786Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cells of the monocyte/macrophage lineage are important for tumour cell migration, invasion and metastasis. Fusion between macrophages and cancer cells in animal models in vitro and in vivo causes hybrids with increased metastatic potential. Primary breast cancer cells were characterized for macrophage antigens to test if phenotypic resemblance to macrophages is related to early distant recurrence. Immunostaining for CD163, MAC387 and CD68 was performed in a breast cancer tissue micro array from 127 patients consequently followed up for a median of 13 years. Tumour-associated macrophages expressed all 3 antigens. The breast cancers expressed CD163 to 48%, MAC387 to 14% while CD68 was not expressed. TGF-β staining intensity was positively related to both CD163 and MAC387 expression. Expression of CD163 in the cancer cells was compared to their DNA ploidy, Nottingham Histological Grade, TNM-stage, node state, presence of estrogen receptors and occurrence of distant metastases and survival. Cancers of a more advanced histological grade expressed CD163 to a higher extent. Cells expressing MAC387 were more common in cancers with a high proportion of CD163 positive cells. Multivariate analysis showed that expression of the macrophage antigen CD163 in breast cancer cells has a prognostic impact on the occurrence of distant metastases and reduced patient survival time.

  • 99.
    Sivik, Tove
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Gunnarsson, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk genetik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Fornander, Tommy
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Skoog, Lambert
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Jansson, Agneta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    17β-hydroxysteroid dehydrogenase type 14 is a predictive marker for tamoxifen response in oestrogen receptor positive breast cancer2012Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 7, s. e40568-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: 17β-hydroxysteroid dehydrogenases (17βHSDs) are important enzymes regulating the pool of bioactive steroids in the breast. The current study was undertaken in order to evaluate implications of 17βHSD14 in breast cancer, measuring 17βHSD14 protein expression in breast tumours.

    Methods: An antibody targeting the 17βHSD14 antigen was generated and validated using HSD17B14-transfected cells and a peptide-neutralising assay. Tissue microarrays with tumours from 912 post-menopausal women diagnosed with lymph node-negative breast cancer, and randomised to adjuvant tamoxifen or no endocrine treatment, were analysed for 17βHSD14 protein expression with immunohistochemistry.

    Results: Results were obtained from 847 tumours. Patients with oestrogen positive tumours with high 17βHSD14 expression had fewer local recurrences when treated with tamoxifen (HR 0.38; 95% C.I. 0.19–0.77, p = 0.007) compared to patients with lower tumoural 17βHSD14 expression, for whom tamoxifen did not reduce the number of local recurrences (HR 1.19; 95% C.I. 0.54–2.59; p = 0.66). No prognostic importance of 17βHSD14 was seen for systemically untreated patients.

    Conclusions: Using a highly specific validated antibody for immunohistochemical analysis of a large number of breast tumours, we have shown that tumoural expression levels of 17βHSD14 can predict the outcome of adjuvant tamoxifen treatment in terms of local recurrence-free survival in patients with lymph node-negative ER+ breast cancer. The results need be verified to confirm any clinical relevance.

  • 100.
    Sivik, Tove
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Fornander, T
    Karolinska Institute.
    Skoog, L
    Karolinska Institute.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Jansson, Agneta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Significance of 17bHSD Type 14 as a Predictive Factor for Adjuvant Tamoxifen Treatment Response in Breast Cancer in CANCER RESEARCH, vol 69, issue 24, pp 596S-597S2009Ingår i: CANCER RESEARCH, 2009, Vol. 69, nr 24, s. 596S-597SKonferensbidrag (Refereegranskat)
    Abstract [en]

    n/a

123 51 - 100 av 123
RefereraExporteraLänk till träfflistan
Permanent länk
Referera
Referensformat
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf