liu.seSök publikationer i DiVA
Ändra sökning
Avgränsa sökresultatet
1 - 29 av 29
RefereraExporteraLänk till träfflistan
Permanent länk
Referera
Referensformat
  • apa
  • 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.
  • 1.
    Johansson, Annelie
    et al.
    Karolinska Inst, Sweden; Univ Hosp, Sweden.
    Yu, Nancy Y.
    Karolinska Inst, Sweden.
    Iftimi, Adina
    Karolinska Inst, Sweden.
    Tobin, Nicholas P.
    Karolinska Inst, Sweden; Univ Hosp, Sweden.
    Van 'T Veer, Laura
    Univ Calif San Francisco, CA USA; Univ Calif San Francisco, CA 94140 USA.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Benz, Christopher C.
    Univ Calif San Francisco, CA 94143 USA; Buck Inst Res Aging, CA USA.
    Fornander, Tommy
    Karolinska Inst, Sweden; Univ Hosp, Sweden.
    Pérez-Tenorio, Gizeh
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Stål, Olle
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Esserman, Laura J.
    Univ Calif San Francisco, CA USA.
    Yau, Christina
    Buck Inst Res Aging, CA USA; Univ Calif San Francisco, CA USA.
    Lindström, Linda S.
    Karolinska Inst, Sweden; Univ Hosp, Sweden.
    Clinical and molecular characteristics of estrogen receptor-positive ultralow risk breast cancer tumors identified by the 70-gene signature2022Ingår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 150, nr 12, s. 2072-2082Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The metastatic potential of estrogen receptor (ER)-positive breast cancers is heterogeneous and distant recurrences occur months to decades after primary diagnosis. We have previously shown that patients with tumors classified as ultralow risk by the 70-gene signature have a minimal long-term risk of fatal breast cancer. Here, we evaluate the previously unexplored underlying clinical and molecular characteristics of ultralow risk tumors in 538 ER-positive patients from the Stockholm tamoxifen randomized trial (STO-3). Out of the 98 ultralow risk tumors, 89% were luminal A molecular subtype, whereas 26% of luminal A tumors were of ultralow risk. Compared to other ER-positive tumors, ultralow risk tumors were significantly (Fishers test, P < .05) more likely to be of smaller tumor size, lower grade, progesterone receptor (PR)-positive, human epidermal growth factor 2 (HER2)-negative and have low Ki-67 levels (proliferation-marker). Moreover, ultralow risk tumors showed significantly lower expression scores of multi-gene modules associated with the AKT/mTOR-pathway, proliferation (AURKA), HER2/ERBB2-signaling, IGF1-pathway, PTEN-loss and immune response (IMMUNE1 and IMMUNE2) and higher expression scores of the PIK3CA-mutation-associated module. Furthermore, 706 genes were significantly (FDR < 0.001) differentially expressed in ultralow risk tumors, including lower expression of genes involved in immune response, PI3K/Akt/mTOR-pathway, histones, cell cycle, DNA repair, apoptosis and higher expression of genes coding for epithelial-to-mesenchymal transition and homeobox proteins, among others. In conclusion, ultralow risk tumors, associated with minimal long-term risk of fatal disease, differ from other ER-positive tumors, including luminal A molecular subtype tumors. Identification of these characteristics is important to improve our prediction of nonfatal vs fatal breast cancer.

    Ladda ner fulltext (pdf)
    fulltext
  • 2.
    Pousette, Jenny
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Johansson, Annelie
    Karolinska Inst, Sweden; Univ Hosp, Sweden.
    Jönsson, Carolin
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Fornander, Tommy
    Karolinska Inst, Sweden; Univ Hosp, Sweden.
    Lindström, Linda S.
    Karolinska Inst, Sweden; Univ Hosp, Sweden.
    Olsson, Hans
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för neurobiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi.
    Perez-Tenorio, Gizeh
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Prognostic and Predictive Significance of Stromal Tumor-Infiltrating Lymphocytes (sTILs) in ER-Positive/HER2-Negative Postmenopausal Breast Cancer Patients2022Ingår i: Cancers, ISSN 2072-6694, Vol. 14, nr 19, artikel-id 4844Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The clinical impact of tumor-infiltrating lymphocytes (TILs) is less known for breast cancer patients with the estrogen receptor-positive (ER+)/human epidermal growth factor receptor-negative (HER−) subtype. Here, we explored the prognostic and predictive value of TILs regarding distant recurrence-free interval (DRFI) and breast cancer-specific survival (BCSS) in 763 postmenopausal patients randomized to receive tamoxifen vs. no systemic treatment. TILs were assessed in whole section tumor samples stained with H&E and divided into low (<10%), intermediate (10–39%), or high (≥40%). High TILs were associated with poor prognostic variables and good prognoses for all patients, but not within the ER+/HER2− group. Within the ER+/HER2− group, high gene expression of CD19 and PD-L1 and high IMMUNE1 score indicated good prognosis in multivariable analysis while high CD8 and CD19 gene expression and high IMMUNE1 score were associated with less tamoxifen benefit. These results indicate that within the ER+/HER2− subtype there could be subsets of patients where expression of specific TIL markers might be used to reveal candidates for immune therapy interventions upon failure of the endocrine therapy.

    Ladda ner fulltext (pdf)
    fulltext
  • 3.
    Johansson, Annelie
    et al.
    Karolinska Inst, Sweden.
    Dar, Huma
    Karolinska Inst, Sweden.
    Veer, Laura J. van t
    Univ Calif San Francisco, CA USA.
    Tobin, Nicholas P.
    Karolinska Inst, Sweden.
    Perez-Tenorio, Gizeh
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Nordenskjöld, Anna
    Gothenburg Univ, Sweden.
    Johansson, Ulla
    Karolinska Univ Hosp, Sweden.
    Hartman, Johan
    Karolinska Inst, Sweden.
    Skoog, Lambert
    Karolinska Inst, Sweden.
    Yau, Christina
    Buck Inst Res Aging, CA USA; Univ Calif San Francisco, CA USA.
    Benz, Christopher C.
    Buck Inst Res Aging, CA USA; Univ Calif San Francisco, CA USA.
    Esserman, Laura J.
    Univ Calif San Francisco, CA USA.
    Stål, Olle
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Fornander, Tommy
    Karolinska Inst, Sweden.
    Lindstrom, Linda S.
    Karolinska Inst, Sweden.
    Twenty-Year Benefit From Adjuvant Goserelin and Tamoxifen in Premenopausal Patients With Breast Cancer in a Controlled Randomized Clinical Trial2022Ingår i: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 40, nr 35, s. 4071-4082Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PURPOSETo assess the long-term (20-year) endocrine therapy benefit in premenopausal patients with breast cancer.METHODSSecondary analysis of the Stockholm trial (STO-5, 1990-1997) randomly assigning 924 premenopausal patients to 2 years of goserelin (3.6 mg subcutaneously once every 28 days), tamoxifen (40 mg orally once daily), combined goserelin and tamoxifen, or no adjuvant endocrine therapy (control) is performed. Random assignment was stratified by lymph node status; lymph node-positive patients (n = 459) were allocated to standard chemotherapy (cyclophosphamide, methotrexate, and fluorouracil). Primary tumor immunohistochemistry (n = 731) and gene expression profiling (n = 586) were conducted in 2020. The 70-gene signature identified genomic low-risk and high-risk patients. Kaplan-Meier analysis, multivariable Cox proportional hazard regression, and multivariable time-varying flexible parametric modeling assessed the long-term distant recurrence-free interval (DRFI). Swedish high-quality registries allowed a complete follow-up of 20 years.RESULTSIn estrogen receptor-positive patients (n = 584, median age 47 years), goserelin, tamoxifen, and the combination significantly improved long-term distant recurrence-free interval compared with control (multivariable hazard ratio [HR], 0.49; 95% CI, 0.32 to 0.75, HR, 0.57; 95% CI, 0.38 to 0.87, and HR, 0.63; 95% CI, 0.42 to 0.94, respectively). Significant goserelin-tamoxifen interaction was observed (P = .016). Genomic low-risk patients (n = 305) significantly benefitted from tamoxifen (HR, 0.24; 95% CI, 0.10 to 0.60), and genomic high-risk patients (n = 158) from goserelin (HR, 0.24; 95% CI, 0.10 to 0.54). Increased risk from the addition of tamoxifen to goserelin was seen in genomic high-risk patients (HR, 3.36; 95% CI, 1.39 to 8.07). Moreover, long-lasting 20-year tamoxifen benefit was seen in genomic low-risk patients, whereas genomic high-risk patients had early goserelin benefit.CONCLUSIONThis study shows 20-year benefit from 2 years of adjuvant endocrine therapy in estrogen receptor-positive premenopausal patients and suggests differential treatment benefit on the basis of tumor genomic characteristics. Combined goserelin and tamoxifen therapy showed no benefit over single treatment. Long-term follow-up to assess treatment benefit is critical.

    Ladda ner fulltext (pdf)
    fulltext
  • 4.
    Dar, Huma
    et al.
    Karolinska Inst, Sweden; Univ Hosp, Sweden.
    Johansson, Annelie
    Karolinska Inst, Sweden; Univ Hosp, Sweden.
    Nordenskjöld, Anna
    Sahlgrens Acad, Sweden; Southern Alvsborg Hosp, Sweden.
    Iftimi, Adina
    Karolinska Inst, Sweden.
    Yau, Christina
    Univ Calif San Francisco, CA USA.
    Perez-Tenorio, Gizeh
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Benz, Christopher
    Univ Calif San Francisco, CA 94143 USA.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Stål, Olle
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Esserman, Laura J.
    Univ Calif San Francisco, CA USA.
    Fornander, Tommy
    Karolinska Inst, Sweden; Univ Hosp, Sweden.
    Lindström, Linda S.
    Karolinska Inst, Sweden; Univ Hosp, Sweden.
    Assessment of 25-Year Survival of Women With Estrogen Receptor-Positive/ERBB2-Negative Breast Cancer Treated With and Without Tamoxifen Therapy A Secondary Analysis of Data From the Stockholm Tamoxifen Randomized Clinical Trial2021Ingår i: JAMA Network Open, E-ISSN 2574-3805, Vol. 4, nr 6, artikel-id e2114904Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    IMPORTANCE Clinically used breast cancer markers, such as tumor size, tumor grade, progesterone receptor (PR) status, and Ki-67 status, are known to be associated with short-term survival, but the association of these markers with long-term (25-year) survival is unclear. OBJECTIVE To assess the association of clinically used breast cancer markers with long-term survival and treatment benefit among postmenopausal women with lymph node-negative, estrogen receptor [ER]-positive and ERBB2-negative breast cancer who received tamoxifen therapy. DESIGN, SETTING, AND PARTICIPANTS This study was a secondary analysis of data from a subset of 565 women with ER-positive/ERBB2-negative breast cancer who participated in the Stockholm tamoxifen (STO-3) randomized clinical trial. The STO-3 clinical trial was conducted from 1976 to 1990 and comprised 1780 postmenopausal women with lymph node-negative breast cancer who were randomized to receive adjuvant tamoxifen therapy or no endocrine therapy. Complete 25-year follow-up data through December 31, 2016, were obtained from Swedish national registers. Immunohistochemical markers were reannotated in 2014. Data were analyzed from April to December 2020. INTERVENTIONS Patients in the original STO-3 clinical trial were randomized to receive 2 years of tamoxifen therapy vs no endocrine therapy. In 1983, patients who received tamoxifen therapy without cancer recurrence during the 2-year treatment and who consented to continued participation in the STO-3 study were further randomized to receive 3 additional years of tamoxifen therapy or no endocrine therapy. MAIN OUTCOMES AND MEASURES Distant recurrence-free interval (DRFI) by clinically used breast cancer markers was assessed using Kaplan-Meier and multivariable Cox proportional hazards analyses adjusted for age, period of primary diagnosis, tumor size (T1a and T1b [T1a/b], T1c, and T2), tumor grade (1-3), PR status (positive vs negative), Ki-67 status (low vs medium to high), and STO-3 clinical trial arm (tamoxifen treatment vs no adjuvant treatment). A recursive partitioning analysis was performed to evaluate which markers were able to best estimate long-term DRFI. RESULTS The study population comprised 565 postmenopausal women (mean [SD] age, 62.0 [5.3] years) with lymph node-negative, ER-positive/ERBB2-negative breast cancer. A statistically significant difference in long-term DRFI was observed by tumor size (88% for T1a/b vs 76% for T1c vs 63% for T2 tumors; log-rank P &lt;.001) and tumor grade (81% for grade 1 vs 77% for grade 2 vs 65% for grade 3 tumors; log-rank P =.02) but not by PR status or Ki-67 status. Patients with smaller tumors (hazard ratio [HR], 0.31 [95% CI, 0.17-0.55] for T1a/b tumors and 0.58 [95% CI, 0.38-0.88] for T1c tumors) and grade 1 tumors (HR, 0.48; 95% CI, 0.24-0.95) experienced a significant reduction in the long-term risk of distant recurrence compared with patients with larger (T2) tumors and grade 3 tumors, respectively. A significant tamoxifen treatment benefitwas observed among patients with larger tumors (HR, 0.53 [95% CI, 0.32-0.89] for T1c tumors and 0.34 [95% CI, 0.16-0.73] for T2 tumors), lower tumor grades (HR, 0.24 [95% CI, 0.07-0.82] for grade 1 tumors and 0.50 [95% CI, 0.31-0.80] for grade 2 tumors), and PR-positive status (HR, 0.38; 95% CI, 0.24-0.62). The recursive partitioning analysis revealed that tumor sizewas the most important characteristic associated with long-term survival, followed by clinical trial arm among patients with larger tumors. CONCLUSIONS AND RELEVANCE This secondary analysis of data from the STO-3 clinical trial indicated that, among the selected subgroup of patients, tumor size followed by tumor grade were the markers most significantly associated with long-term survival. Furthermore, a significant long-term tamoxifen treatment benefit was observed among patients with larger tumors, lower tumor grades, and PR-positive tumors.

    Ladda ner fulltext (pdf)
    fulltext
  • 5.
    Sandström, Josefine
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Balian, Alien
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Lockowandt, Rebecca
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Fornander, Tommy
    Karolinska Inst, Sweden.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Lindstrom, Linda
    Karolinska Inst, Sweden.
    Perez Tenorio, Gizeh
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Stål, Olle
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    IP6K2 predicts favorable clinical outcome of primary breast cancer2021Ingår i: Molecular and clinical oncology, ISSN 2049-9450, E-ISSN 2049-9469, Vol. 14, nr 5, artikel-id 94Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The inositol hexakisphosphate kinase (IP6K) 1 and 2 genes are localized at 3p21.31, a highly altered gene-dense chromosomal region in cancer. The IP6Ks convert IP6 to IP7, which inhibits activation of the tumor-promoting PI3K/Akt/mTOR signaling pathway. IP6K2 has been suggested to be involved in p53-induced apoptosis, while IP6K1 may stimulate tumor growth and migration. The present study aimed to elucidate the role of the two IP6Ks in predicting outcome in patients with breast cancer. To the best of our knowledge, the role of IP6K was analyzed for the first time in tumors from three cohorts of patients with breast cancer; one Swedish low-risk cohort, one Dutch cohort and the TCGA dataset. Analyses of gene -and protein expression and subcellular localization were included. IP6K2 gene expression was associated with ER positivity and nuclear p-Akt. Improved prognosis was detected with high IP6K2 gene expression compared with low IP6K2 gene expression in systemically untreated patients in the Swedish low-risk and Dutch cohorts. In the TCGA dataset, IP6K2 prognostic value was significant when selecting for tumors with wild-type TP53. A multivariable analysis testing IP6K2 against other cancer-related genes at 3p.21.31, including IP6K1 and clinical biomarkers, revealed that IP6K2 was associated with decreased risk of distant recurrence. IP6K1 was associated with increased risk of distant recurrence in the multivariable test and protein analysis revealed trends of worse prognosis with high IP6K1 in the cytoplasm. The expression levels of IP6K1 and IP6K2 were associated to a high extent; however, a diverging prognostic value of the two genes was observed in breast cancer. The present data suggest that IP6K2 can be a favorable prognostic factor, while IP6K1 may not be.

    Ladda ner fulltext (pdf)
    fulltext
  • 6.
    Magic, Zeljana
    et al.
    Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US. Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
    Sandström, Josefine
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Perez Tenorio, Gizeh
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Ephrin-B2 inhibits cell proliferation and motility in vitro and predicts longer metastasis-free survival in breast cancer2019Ingår i: International Journal of Oncology, ISSN 1019-6439, E-ISSN 1791-2423, Vol. 55, nr 6, s. 1275-1286Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The tyrosine kinase receptor EphB4 and its ligand ephrin-B2 interact through cell-to-cell contacts. Upon interaction, EphB4 transmits bidirectional signals. A forward signal inside EphB4-expressing cells is believed to suppress tumor growth, while inside the ephrin-expressing cells, an oncogenic reverse signal arises. In breast cancer cells with a high EphB4 receptor expression the forward signal is low, in part due to the low expression of the ligand ephrin-B2. Therefore, we hypothesized that by re-introducing the ligand in EphB4-positive cells, tumor suppression could be induced by the stimulation of the forward signal. This question was addressed in vitro by the stable lentiviral infection of breast cancer cells with either wild-type EFNB2 or with a mutant EFNB2-5F, unable to transmit reverse signaling. Furthermore, we investigated ephrin-B and EphB4 protein expression in 216 paraffin-embedded tumors using immunohistochemistry. The in vitro results indicated that ephrin-B2 expression was associated with a lower cell proliferation, migration and motility compared with the control cells. These effects were more pronounced when the cells lacked the ability to transmit the reverse signal (B2-5F). In clinical material, ephrin-B protein expression was associated with a positive estrogen receptor (ER) status, a low HER-2 expression and was negatively associated with Nottingham histologic grade (NHG) III. Ephrin-B expression indicated a good prognosis, whereas EphB4 expression was associated with a shorter metastasis-free survival in univariate and multivariate analysis. Furthermore, the prognostic value of EFNB2 and EPHB4 was confirmed at the gene expression level in public datasets. Thus, on the whole, the findings of this study suggest that ephrin-B2 expression is associated with less proliferation and lower motility of breast cancer cells and with a longer patient survival in breast cancer.

    Ladda ner fulltext (pdf)
    fulltext
  • 7.
    Ellegård, Sander
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. 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 Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Pérez-Tenorio, Gizeh
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Fagerström, Victor
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US. Department of Surgery, Kalmar Hospital, Kalmar.
    Gårsjö, Jon
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Gert, Krista
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Sundquist, Marie
    Department of Surgery, Kalmar Hospital, Kalmar.
    Malmström, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Wingren, Sten
    Department of Clinical Medicine, School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Elander, Nils
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Hallbeck, Anna-Lotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. 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 Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    ERBB2 and PTPN2 gene copy numbers as prognostic factors in HER2-positive metastatic breast cancer treated with trastuzumab2019Ingår i: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 17, nr 3, s. 3371-3381Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Trastuzumab has markedly improved the treatment and long-term prognosis of patients with HER2-positive breast cancer. A frequent clinical challenge in patients with relapsing and/or metastatic disease is de novo or acquired trastuzumab resistance, and to date no predictive biomarkers for palliative trastuzumab have been established. In the present study, the prognostic values of factors involved in the HER2-associated PI3K/Akt signalling pathway were explored. The first 46 consecutive patients treated at the Department of Oncology, Linkoping University Hospital between 2000 and 2007 with trastuzumab for HER2-positive metastatic breast cancer were retrospectively included. The gene copy number variation and protein expression of several components of the PI3K/Akt pathway were assessed in the tumour tissue and biopsy samples using droplet digital polymerase chain reaction and immunohistochemistry. Patients with tumours displaying a high-grade ERBB2 (HER2) amplification level of amp;gt;= 6 copies had a significantly improved overall survival hazard ratio [(HR)=0.4; 95%, confidence interval (CI): 0.2-0.9] and progression-free survival (HR=0.3; 95% CI: 0.1-0.7) compared with patients with tumours harbouring fewer ERBB2 copies. High-grade ERBB2 amplification was significantly associated with the development of central nervous system metastases during palliative treatment. Copy gain (amp;gt;= 3 copies) of the gene encoding the tyrosine phosphatase PTPN2 was associated with a shorter overall survival (HR=2.0; 95% CI: 1.0-4.0) and shorter progression-free survival (HR=2.1; 95% CI: 1.0-4.1). In conclusion, high ERBB2 amplification level is a potential positive prognostic factor in trastuzumab-treated HER2-positive metastatic breast cancer, whereas PTPN2 gain is a potential negative prognostic factor. Further studies are warranted on the role of PTPN2 in HER2 signalling.

    Ladda ner fulltext (pdf)
    fulltext
  • 8.
    Veenstra, Cynthia
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Karlsson, Elin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Mirwani, Sanam Mirwani
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Fornander, Tommy
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Perez Tenorio, Gizeh
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    The effects of PTPN2 loss on cell signalling and clinical outcome in relation to breast cancer subtype2019Ingår i: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 145, nr 7, s. 1845-1856Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PurposeThe protein tyrosine phosphatase PTPN2 dephosphorylates several tyrosine kinases in cancer-related signalling pathways and is thought to be a tumour suppressor. As PTPN2 is not frequently studied in breast cancer, we aimed to explore the role of PTPN2 and the effects of its loss in breast cancer.MethodsProtein expression and gene copy number of PTPN2 were analysed in a cohort of pre-menopausal breast cancer patients with immunohistochemistry and droplet digital PCR, respectively. PTPN2 was knocked down in three cell lines, representing different breast cancer subtypes, with siRNA transfection. Several proteins related to PTPN2 were analysed with Western blot.ResultsLow PTPN2 protein expression was found in 50.2% of the tumours (110/219), gene copy loss in 15.4% (33/214). Low protein expression was associated with a higher relapse rate in patients with Luminal A and HER2-positive tumours, but not triple-negative tumours. In vitro studies further suggested a subtype-specific role of PTPN2. Knockdown of PTPN2 had no effect on the triple-negative cell line, whilst knockdown in MCF7 inhibited phosphorylation of Met and promoted that of Akt. Knockdown in SKBR3 led to increased Met phosphorylation and decreased Erk phosphorylation as well as EGF-mediated STAT3 activation.ConclusionWe confirm previous studies showing that the PTPN2 protein is lost in half of the breast cancer cases and gene deletion occurs in 15-18% of the cases. Furthermore, the results suggest that the role of PTPN2 is subtype-related and should be further investigated to assess how this could affect breast cancer prognosis and treatment response.

    Ladda ner fulltext (pdf)
    fulltext
  • 9.
    Zardavas, Dimitrios
    et al.
    Breast Int Grp, Belgium.
    te Marvelde, Luc
    Canc Council, Australia.
    Milne, Roger L.
    Canc Council, Australia; Univ Melbourne, Australia.
    Fumagalli, Debora
    Breast Int Grp, Belgium.
    Fountzilas, George
    Aristotle Univ Thessaloniki, Greece.
    Kotoula, Vassiliki
    Aristotle Univ Thessaloniki, Greece.
    Razis, Evangelia
    Hygeia Hosp, Greece.
    Papaxoinis, George
    Hippokrateion Hosp, Greece.
    Joensuu, Heikki
    Helsinki Univ Hosp, Finland; Univ Helsinki, Finland.
    Moynahan, Mary Ellen
    Mem Sloan Kettering Canc Ctr, NY 10021 USA.
    Hennessy, Bryan T.
    Beaumont Hosp, Ireland; Royal Coll Surg, Ireland.
    Bieche, Ivan
    Curie Inst, France.
    Saal, Lao H.
    Lund Univ, Sweden.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Iacopetta, Barry
    Univ Western Australia, Australia.
    Jensen, Jeanette Dupont
    Univ Southern Denmark, Denmark.
    OToole, Sandra
    Garvan Inst Med Res, Australia.
    Lopez-Knowles, Elena
    Garvan Inst Med Res, Australia; Royal Marsden NHS Trust, England; Inst Canc Res, England.
    Barbaraeschi, Mattia
    Santa Chiara Hosp, Italy.
    Noguchi, Shinzaburo
    Osaka Univ, Japan.
    Azim, Hatem A. Jr.
    Amer Univ Beirut, Lebanon.
    Lerma, Enrique
    Univ Autonoma Barcelona, Spain.
    Bachelot, Thomas
    Ctr Rech Cancerol Lyon, France.
    Wang, Qing
    Linköpings universitet.
    Perez Tenorio, Gizeh
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    de Velde, Cornelis J. H. Can
    Leiden Univ, Netherlands.
    Rea, Daniel W.
    Univ Birmingham, England.
    Sabine, Vicky
    Univ Guelph, Canada.
    Bartlett, John M. S.
    Ontario Inst Canc Res, Canada.
    Sotiriou, Christos
    Univ Libre Bruxelles, Belgium.
    Michiels, Stefan
    Gustave Roussy, France; Univ Paris Saclay, France.
    Loi, Sherene
    Univ Melbourne, Australia.
    Tumor PIK3CA Genotype and Prognosis in Early-Stage Breast Cancer: A Pooled Analysis of Individual Patient Data2018Ingår i: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 36, nr 10, s. 981-+Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PurposePhosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations are frequently observed in primary breast cancer. We evaluated their prognostic relevance by performing a pooled analysis of individual patient data.Patients and MethodsAssociations between PIK3CA status and clinicopathologic characteristics were tested by applying Cox regression models adjusted for age, tumor size, nodes, grade, estrogen receptor (ER) status, human epidermal growth factor receptor 2 (HER2) status, treatment, and study. Invasive disease-free survival (IDFS) was the primary end point; distant disease-free survival (DDFS) and overall survival (OS) were also assessed, overall and by breast cancer subtypes.ResultsData from 10,319 patients from 19 studies were included (median OS follow-up, 6.9 years); 1,787 patients (17%) received chemotherapy, 4,036 (39%) received endocrine monotherapy, 3,583 (35%) received both, and 913 (9%) received none or their treatment was unknown. PIK3CA mutations occurred in 32% of patients, with significant associations with ER positivity, increasing age, lower grade, and smaller size (all P amp;lt; .001). Prevalence of PIK3CA mutations was 18%, 22%, and 37% in the ER-negative/HER2-negative, HER2-positive, and ER-positive/HER2-negative subtypes, respectively. In univariable analysis, PIK3CA mutations were associated with better IDFS (HR, 0.77; 95% CI, 0.71 to 0.84; P amp;lt; .001), with evidence for a stronger effect in the first years of follow-up (0 to 5 years: HR, 0.73; 95% CI, 0.66 to 0.81; P amp;lt; .001; 5 to 10 years: HR, 0.82; 95% CI, 0.68 to 0.99; P = .037); amp;gt; 10 years: (HR, 1.15; 95% CI, 0.84 to 1.58; P = .38; P heterogeneity = .02). In multivariable analysis, PIK3CA genotype remained significant for improved IDFS (P = .043), but not for the DDFS and OS end points.ConclusionIn this large pooled analysis, PIK3CA mutations were significantly associated with a better IDFS, DDFS, and OS, but had a lesser prognostic effect after adjustment for other prognostic factors. (C) 2018 by American Society of Clinical Oncology

    Ladda ner fulltext (pdf)
    fulltext
  • 10.
    Husa, Anna-Maria
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. St Anna Kinderkrebsforsch eV, Austria.
    Magic, Zeljana
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Larsson, Malin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Fornander, Tommy
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Perez-Tenorio, Gizeh
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    EPH/ephrin profile and EPHB2 expression predicts patient survival in breast cancer2016Ingår i: Oncotarget, E-ISSN 1949-2553, Vol. 7, nr 16, s. 21362-21380Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The EPH and ephrins function as both receptor and ligands and the output on their complex signaling is currently investigated in cancer. Previous work shows that some EPH family members have clinical value in breast cancer, suggesting that this family could be a source of novel clinical targets. Here we quantified the mRNA expression levels of EPH receptors and their ligands, ephrins, in 65 node positive breast cancer samples by RT-PCR with TaqMan (R) Micro Fluidics Cards Microarray. Upon hierarchical clustering of the mRNA expression levels, we identified a subgroup of patients with high expression, and poor clinical outcome. EPHA2, EPHA4, EFNB1, EFNB2, EPHB2 and EPHB6 were significantly correlated with the cluster groups and particularly EPHB2 was an independent prognostic factor in multivariate analysis and in four public databases. The EPHB2 protein expression was also analyzed by immunohistochemistry in paraffin embedded material (cohort 2). EPHB2 was detected in the membrane and cytoplasmic cell compartments and there was an inverse correlation between membranous and cytoplasmic EPHB2. Membranous EPHB2 predicted longer breast cancer survival in both univariate and multivariate analysis while cytoplasmic EPHB2 indicated shorter breast cancer survival in univariate analysis. Concluding: the EPH/EFN cluster analysis revealed that high EPH/EFN mRNA expression is an independent prognostic factor for poor survival. Especially EPHB2 predicted poor breast cancer survival in several materials and EPHB2 protein expression has also prognostic value depending on cell localization.

    Ladda ner fulltext (pdf)
    fulltext
  • 11.
    Veenstra, Cynthia
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Perez-Tenorio, Gizeh
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Stelling, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Karlsson, Elin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Mirwani Mirwani, Sanam
    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.
    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. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Met and its ligand HGF are associated with clinical outcome in breast cancer2016Ingår i: Oncotarget, E-ISSN 1949-2553, Vol. 7, nr 24, s. 37145-37159Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Few biomarkers exist to predict radiotherapy response in breast cancer. In vitro studies suggest a role for Met and its ligand HGF. To study this suggested role, MET and HGF gene copy numbers were determined by droplet digital PCR in tumours from 205 pre-menopausal and 184 post-menopausal patients, both cohorts randomised to receive either chemo-or radiotherapy. MET amplification was found in 8% of the patients in both cohorts and HGF amplification in 7% and 6% of the patients in the pre-and post-menopausal cohort, respectively. Met, phosphorylated Met (pMet), and HGF protein expression was determined by immunohistochemistry in the premenopausal cohort. Met, pMet, and HGF was expressed in 33%, 53%, and 49% of the tumours, respectively. MET amplification was associated with increased risk of distant recurrence for patients receiving chemotherapy. For the pre-menopausal patients, expression of cytoplasmic pMet and HGF significantly predicted benefit from radiotherapy in terms of loco-regional recurrence. Similar trends were seen for MET and HGF copy gain. In the post-menopausal cohort, no significant association of benefit from radiotherapy with neither genes nor proteins was found. The present results do not support that inhibition of Met prior to radiotherapy would be favourable for pre-menopausal breast cancer, as previously suggested.

    Ladda ner fulltext (pdf)
    fulltext
  • 12.
    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.

    Ladda ner fulltext (pdf)
    fulltext
  • 13.
    Bostner, Josefine
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Karlsson, Elin
    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.
    Bivik Eding, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Perez-Tenorio, Gizeh
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Franzén, Hanna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Konstantinell, Aelita
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Fornander, Tommy
    Karolinska University Hospital, Sweden.
    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.
    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.
    S6 kinase signaling: tamoxifen response and prognostic indication in two breast cancer cohorts2015Ingår i: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 22, nr 3, s. 331-343Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Detection of signals in the mammalian target of rapamycin (mTOR) and the estrogen receptor (ER) pathways may be a future clinical tool for the prediction of adjuvant treatment response in primary breast cancer. Using immunohistological staining, we investigated the value of the mTOR targets p70-S6 kinase (S6K) 1 and 2 as biomarkers for tamoxifen benefit in two independent clinical trials comparing adjuvant tamoxifen with no tamoxifen or 5 years versus 2 years of tamoxifen treatment. In addition, the prognostic value of the S6Ks was evaluated. We found that S6K1 correlated with proliferation, HER2 status, and cytoplasmic AKT activity, whereas high protein expression levels of S6K2 and phosphorylated (p) S6K were more common in ER-positive, and low-proliferative tumors with pAKT-s473 localized to the nucelus. Nuclear accumulation of S6K1 was indicative of a reduced tamoxifen effect (hazard ratio (HR): 1.07, 95% CI: 0.53-2.81, P=0.84), compared with a significant benefit from tamoxifen treatment in patients without tumor S6K1 nuclear accumulation (HR: 0.42, 95% CI: 0.29-0.62, Pless than0.00001). Also S6K1 and S6K2 activation, indicated by pS6K-t389 expression, was associated with low benefit from tamoxifen (HR: 0.97, 95% CI: 0.50-1.87, P=0.92). In addition, high protein expression of S6K1, independent of localization, predicted worse prognosis in a multivariate analysis, P=0.00041 (cytoplasm), P=0.016 (nucleus). In conclusion, the mTOR-activated kinases S6K1 and S6K2 interfere with proliferation and response to tamoxifen. Monitoring their activity and intracellular localization may provide biomarkers for breast cancer treatment, allowing the identification of a group of patients less likely to benefit from tamoxifen and thus in need of an alternative or additional targeted treatment.

    Ladda ner fulltext (pdf)
    fulltext
  • 14.
    Aguilar, Helena
    et al.
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Urruticoechea, Ander
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Halonen, Pasi
    The Netherlands Cancer Institute, Amsterdam.
    Kiyotani, Kazuma
    Center for Genomic Medicine, RIKEN, Yokohama, Japan.
    Mushiroda, Taisei
    Center for Genomic Medicine, RIKEN, Yokohama, Japan.
    Barril, Xavier
    University of Barcelona, Catalonia, Spain.
    Serra-Musach, Jordi
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Islam, Abul
    University of Dhaka, Bangladesh.
    Caizzi, Livia
    Centre for Genomic Regulation (CRG), Barcelona, Catalonia, Spain.
    Di Croce, Luciano
    Centre for Genomic Regulation (CRG), Barcelona, Catalonia, Spain.
    Nevedomskaya, Ekaterina
    The Netherlands Cancer Institute, Amsterdam.
    Zwart, Wilbert
    The Netherlands Cancer Institute, Amsterdam.
    Bostner, Josefine
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Karlsson, Elin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Perez-Tenorio, Gizeh
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Fornander, Tommy
    Karolinska University Hospital, Stockholm South General Hospital, Sweden.
    Sgroi, Dennis C
    Massachusetts General Hospital, Boston, USA.
    Garcia-Mata, Rafael
    University of North Carolina at Chapel Hill, USA.
    Jansen, Maurice Phm
    Cancer Institute, Rotterdam, The Netherlands.
    García, Nadia
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Bonifaci, Núria
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Climent, Fina
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Soler, María Teresa
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Rodríguez-Vida, Alejo
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Gil, Miguel
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Brunet, Joan
    Hospital Josep Trueta, Girona, Catalonia, Spain.
    Martrat, Griselda
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Gómez-Baldó, Laia
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Extremera, Ana I
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Figueras, Agnes
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Balart, Josep
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Clarke, Robert
    Georgetown University Medical Center, Washington, DC, USA.
    Burnstein, Kerry L
    University of Miami, Miller School of Medicine, Miami, FL, USA.
    Carlson, Kathryn E
    University of Illinois, Urbana, USA.
    Katzenellenbogen, John A
    University of Illinois, Urbana, USA.
    Vizoso, Miguel
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Esteller, Manel
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain .
    Villanueva, Alberto
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Rodríguez-Peña, Ana B
    CSIC-University of Salamanca, Spain.
    Bustelo, Xosé R
    CSIC-University of Salamanca, Spain.
    Nakamura, Yusuke
    University of Tokyo, Japan.
    Zembutsu, Hitoshi
    University of Tokyo, Japan.
    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.
    Beijersbergen, Roderick L
    The Netherlands Cancer Institute, Amsterdam .
    Pujana, Miguel Angel
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    VAV3 mediates resistance to breast cancer endocrine therapy2014Ingår i: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 16, nr 3, s. R53-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    INTRODUCTION: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor alpha (ERalpha) are among the most effective systemic treatments for ERalpha-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ERalpha transcriptional regulatory plasticity. Here, we identify VAV3 as a critical component in this process.

    METHODS: A cell-based chemical compound screen was carried out to identify therapeutic strategies against resistance to endocrine therapy. Binding to ERalpha was evaluated by molecular docking analyses, an agonist fluoligand assay, and short-hairpin (sh) RNA-mediated protein depletion. Microarray analyses were performed to identify altered gene expression. Western blot of signaling and proliferation markers and shRNA-mediated protein depletion in viability and clonogenic assays were performed to delineate the role of VAV3. Genetic variation in VAV3 was assessed for association with the response to tamoxifen. Immunohistochemical analyses of VAV3 were carried out to determine the association with therapy response and different tumor markers. An analysis of gene expression association with drug sensitivity was carried out to identify a potential therapeutic approach based on differential VAV3 expression.

    RESULTS: The compound YC-1 was found to comparatively reduce the viability of cell models of acquired resistance. This effect was probably not due to activation of its canonical target (soluble guanylyl cyclase) but instead a result of binding to ERalpha. VAV3 was selectively reduced upon exposure to YC-1 or ERalpha depletion and, accordingly, VAV3 depletion comparatively reduced the viability of cell models of acquired resistance. In the clinical scenario, germline variation in VAV3 was associated with response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value = 8.4 x 10-4). The allele association combined with gene expression analyses indicated that low VAV3 expression predicts better clinical outcome. Conversely, high nuclear VAV3 expression in tumor cells was associated with poorer endocrine therapy response. Based on VAV3 expression levels and the response to erlotinib in cancer cell lines, targeting EGFR signaling may be a promising therapeutic strategy.

    CONCLUSIONS: This study proposes VAV3 as a biomarker and rationale signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer.

    Ladda ner fulltext (pdf)
    fulltext
  • 15.
    Fohlin, Helena
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för hälso- och vårdutveckling, Regionalt cancercentrum.
    Perez-Tenorio, Gizeh
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Fornander, Tommy
    Karolinska University Hospital, Sweden.
    Skoog, Lambert
    Karolinska University Hospital, 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.
    Carstensen, John
    Linköpings universitet, Institutionen för medicin och hälsa, Hälsa och samhälle. Linköpings universitet, Hälsouniversitetet.
    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.
    Akt2 expression is associated with good long-term prognosis in oestrogen receptor positive breast cancer2013Ingår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 49, nr 6, s. 1196-1204Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction

    Akt is a signalling modulator for many cellular processes, including metabolism, cell proliferation, cell survival and cell growth. Three isoforms of Akt have been identified, but only a few studies have concerned the isoform-specific roles in the prognosis of breast cancer patients. The aim of this study was to investigate the prognostic value of v-akt murine thymoma viral oncogene homologue 1 (Akt1) and v-akt murine thymoma viral oncogene homologue 2 (Akt2) in oestrogen receptor positive (ER+) and oestrogen receptor negative (ER–) breast cancer with long-term follow-up.

    Material and methods

    The expression of Akt in tumour tissue was analysed with immunohistochemistry in a cohort of 272 postmenopausal patients with stage II breast cancer. The median follow-up time was 19 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the Cox’s proportional hazards model.

    Results

    The risk of distant recurrence was reduced for patients with ER+ tumours expressing Akt2 compared to patients with no Akt2 expression (HR = 0.49, 95% CI 0.29–0.82, p = 0.007). When adjusting for important clinical tumour characteristics and treatment, Akt2 was still an independent prognostic factor (HR = 0.38, 95% CI 0.21–0.68, p = 0.001) and the association remained long-term. The prognostic value of Akt2 increased with higher oestrogen receptor levels from no effect among patients with ER– tumours to 68% risk reduction for the group with high ER-levels (P for trend = 0.042). Akt1 showed no significant prognostic information.

    Conclusion

    Our results indicate that Akt2 expression is associated with a lower distant recurrence rate for patients with ER+ tumours and that this association remains long-term. The prognostic value of Akt2 increases with higher oestrogen receptor expression, motivating further mechanistic studies on the role of Akt2 in ER+ breast cancer.

    Ladda ner fulltext (pdf)
    fulltext
  • 16.
    Falivelli, Giulia
    et al.
    Sanford-Burnham Medical Research Institute, San Diego, California, USA / Department Pharmacology, University of Bologna, Bologna, Italy.
    Lisabeth, Erika Mathes
    Sanford-Burnham Medical Research Institute, San Diego, California, USA.
    Rubio de la Torre, Elena
    Sanford-Burnham Medical Research Institute, San Diego, California, USA.
    Perez-Tenorio, Gizeh
    Sanford-Burnham Medical Research Institute, San Diego, California, USA.
    Tosato, Giovanna
    Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
    Salvucci, Ombretta
    Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
    Pasquale, Elena B
    Sanford-Burnham Medical Research Institute, San Diego, California, USA / Department of Pathology, University of California San Diego, San Diego, California, USA.
    Attenuation of eph receptor kinase activation in cancer cells by coexpressed ephrin ligands2013Ingår i: PLOS ONE, E-ISSN 1932-6203, Vol. 8, nr 11, s. e81445-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Eph receptor tyrosine kinases mediate juxtacrine signals by interacting "in trans" with ligands anchored to the surface of neighboring cells via a GPI-anchor (ephrin-As) or a transmembrane segment (ephrin-Bs), which leads to receptor clustering and increased kinase activity. Additionally, soluble forms of the ephrin-A ligands released from the cell surface by matrix metalloproteases can also activate EphA receptor signaling. Besides these trans interactions, recent studies have revealed that Eph receptors and ephrins coexpressed in neurons can also engage in lateral "cis" associations that attenuate receptor activation by ephrins in trans with critical functional consequences. Despite the importance of the Eph/ephrin system in tumorigenesis, Eph receptor-ephrin cis interactions have not been previously investigated in cancer cells. Here we show that in cancer cells, coexpressed ephrin-A3 can inhibit the ability of EphA2 and EphA3 to bind ephrins in trans and become activated, while ephrin-B2 can inhibit not only EphB4 but also EphA3. The cis inhibition of EphA3 by ephrin-B2 implies that in some cases ephrins that cannot activate a particular Eph receptor in trans can nevertheless inhibit its signaling ability through cis association. We also found that an EphA3 mutation identified in lung cancer enhances cis interaction with ephrin-A3. These results suggest a novel mechanism that may contribute to cancer pathogenesis by attenuating the tumor suppressing effects of Eph receptor signaling pathways activated by ephrins in trans.

    Ladda ner fulltext (pdf)
    fulltext
  • 17.
    Bostner, Josefine
    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.
    Bivik, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Perez-Tenorio, Gizeh
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Franzén, Hanna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Konstantinell, Aelita
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Fornander, Tommy
    Karolinska 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.
    S6 kinase signaling and tamoxifen response in breast cancer cells and in two randomized breast cancer cohorts2013Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Detecting signals in the mammalian target of rapamycin (mTOR), and the estrogen receptor (ER) pathways for prediction of treatment response may be a future clinical tool in primary breast cancer. Here, we investigated the validity and value of the mTOR targets p70-S6 kinase (S6K) 1 and 2 as biomarkers for tamoxifen sensitivity in vitro and in two independent tamoxifen randomized postmenopausal breast cancer cohorts. In addition, the prognostic value of the S6Ks was evaluated. A simultaneous knockdown of the S6Ks in ER-positive breast cancer cells resulted in G1 arrest, and tamoxifen-induced G1 arrest was in part S6K1+S6K2 dependent, suggesting separate roles in proliferation and in tamoxifen response. We found S6K1 to correlate with HER2 and cytoplasmic Akt activity, whereas S6K2 and phosphorylated S6K were closer connected with ER positivity, low proliferation and nucleic p-Akt. Treatment prediction and prognosis were evaluated by immunohistochemical staining. Nuclear accumulation of S6K1 was indicative of a reduced tamoxifen treatment effect, compared with a significant benefit from tamoxifen treatment in patients without tumor S6K1 nuclear accumulation. Patients with a combination of S6K1 nuclear accumulation and S6K2 cytoplasmic accumulation in the tumor cells had no tamoxifen benefit. Also, S6K1 and S6K2 activation, indicated by p-S6K-t389 expression, was associated with low benefit from tamoxifen compared with untreated patients. In addition, high protein expression of S6K1, independent of localization, predicted worse prognosis. This was not evident for variations in S6K2 or p-S6K-t389 expression.

    In conclusion, the mTOR targeted kinases S6K1 and S6K2 interfere with proliferation and response to tamoxifen. Monitoring their activity andintracellular localization may provide biomarkers for breast cancer treatment, allowing for identification of a group of patients less likely tobenefit from tamoxifen and thus in need of an alternative or additional treatment.

  • 18.
    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.

    Ladda ner fulltext (pdf)
    fulltext
  • 19.
    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.

    Ladda ner fulltext (pdf)
    fulltext
  • 20.
    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.

    Ladda ner fulltext (pdf)
    fulltext
  • 21.
    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

  • 22.
    Miller, Todd W
    et al.
    Vanderbilt University.
    Narasanna, Archana
    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.
    Gonzalez-Angulo, Ana M
    University of Texas.
    Hennessy, Bryan T
    University of Texas.
    Mills, Gordon B
    University of Texas.
    Kennedy, J Phillip
    Vanderbilt University.
    Lindsley, Craig W
    Vanderbilt University.
    Arteaga, Carlos L
    Vanderbilt University.
    Loss of Phosphatase and Tensin Homologue Deleted on Chromosome 10 Engages ErbB3 and Insulin-Like Growth Factor-I Receptor Signaling to Promote Antiestrogen Resistance in Breast Cancer2009Ingår i: CANCER RESEARCH, ISSN 0008-5472, Vol. 69, nr 10, s. 4192-4201Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Knockdown of the tumor suppressor phosphatase Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) with shRNA in three estrogen receptor (ER)-positive breast cancer cell lines resulted in increased phosphatidylinositol-3 kinase (PI3K) and AKT activities, resistance to tamoxifen and fulvestrant, and hormone-independent growth. PTEN knockdown induced the up-regulation of ER transcriptional activity in MCF-7 cells but decreased ER protein levels and transcriptional activity in T47D and MDA-361 cells. Tamoxifen and fulvestrant treatment inhibited estradiol-induced Ell transcriptional activity in all shPTEN cell lines but did not abrogate the increased cell proliferation induced by PTEN knockdown. PTEN knockdown increased basal and ligand-induced activation of the insulin-like growth factor-I (IGF-I) and ErbB3 receptor tyrosine kinases, and prolonged the association of the p85 PI3K subunit with the IGF-I receptor (IGF-IR) effector insulin receptor substrate-1 and with ErbB3, implicating VITA in the modulation of Signaling upstream of PI3K. Consistent with these data, PTEN levels inversely correlated with levels of tyrosine-phosphorylated IGF-IR in tissue lysate arrays of primary breast cancers. Inhibition of IGF-IR and/or ErbB2-mediated activation of ErbB3 with tyrosine kinase inhibitors restored hormone dependence and the growth inhibitory effect of tamoxifen and fulvestrant. oil shPTEN cells, suggesting that cotargeting both Ell and receptor tyrosine kinase pathways holds promise for the treatment of patients with ER+, PTEN-deficient breast cancers.

  • 23. Beställ onlineKöp publikationen >>
    Pérez-Tenorio, Gizeh
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Alterations in the PI3K/AKT Signaling Pathway and Response to Adjuvant Treatment in Breast Cancer2008Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [sv]

    Bröstcancer är en vanlig sjukdom och dödsorsak bland kvinnor i Sverige. Könshormonet östrogen tillsammas med cellernas receptorer för hormonet spelar en viktig roll för bröstcancerutvecklingen. Därför behandlas denna sjukdom med anti-hormonella substanser inriktade mot hämning av östrogensyntes/östrogen receptorn. Tamoxifen är den vanligaste formen av anti-östrogenbehandling som används efter operation. Tamoxifenbehandling förbättrar betydligt 5-årsöverlevnaden hos patienter med östrogenreceptorpositiva tumörer. Emellertid finns det patienter som återkommer med metastaser efter en tid. I det här projektet studerar vi andra receptorer samt deras signalvägar som kan aktivera östrogenreceptorn och därmed orsaka tamoxifenresistens.

    En sådan receptor är HER-2 vilken överuttrycks i 15-20% vid bröstumörer. HER-2 receptorn kan rekrytera proteiner med enzymatisk aktivitet, till exempel PI3K. PI3K aktiverar ett annat enzym, AKT, vilket är inblandat i en kaskad som leder till tumörtillväxt och tumöröverlevnad (genom till exempel aktivering av östrogenreceptorn). Våra resultat hitills visar att patienter med aktiverat AKT (pAKT) har större risk att få metastaser och därmed sämre överlevnad än patienter utan pAKT, detta trots hormonell behandling. I större material där HER-2 proteinuttrycket korrelerar med pAKT har vi också funnit att patienter med AKTnegativa tumörer kunde dra nytta av både tamoxifen och strålbehandling. Vi har även undersökt PIK3CA genen (som kodar för en del av PI3K) och hittat mutationer i 24% av bröstumörerna. Det är dock ännu oklart hur dessa mutationer ska tas hänsyn till för att kunna bestämma en effektiv behandling. PTEN är ett annat enzym som motverkar PI3K-aktivitet. Bortfall av PTEN förekommer ofta i bröstcancer och  har associerats med PI3K/AKT aktivering. I vårt material var PTEN-förlust frekvent (37%) och associerades med PIK3CA mutationer. PTEN förlust som ensam faktor eller tillsammans med PIK3CA mutationer ökade strålkänslighet. Andra proteiner som är inblandade i PI3K signalvägen är S6K1 och S6K2 och dessa har betydelse för cellens proteinsyntes. Nyligen har vi kunnat visa att generna för både S6K1/2 finns i många kopior (genamplifering) I tumörcellerna hos bröstcancerpatienter. Dessutom fanns det ett positivt samband mellan S6K1/2 amplifiering och amplifiering av andra kända cancergener (som t. ex HER-2 och cyclin D1) men förhållandet till PIK3CA-mutationer var det omvända. Patienter med antigen S6K1 eller HER-2 amplifierade tumörer svarade dåligt på strålbehandling men skulle möjligen kunna behandlas med en specifik substans riktad mot S6K1 eller HER-2. Ett ökat antal kopior av S6K2 indikerade dålig prognos men bra nytta av tamoxifen. Våra resultat visar att PI3K/AKT signalvägen ofta är aktiverad vid bröstcancer och skulle kunna vara en viktig måltavla för behandling.

    Delarbeten
    1. Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients
    Öppna denna publikation i ny flik eller fönster >>Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients
    2002 (Engelska)Ingår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 86, nr 4, s. 540-545Artikel i tidskrift (Refereegranskat) Published
    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

    Nyckelord
    Breast cancer, endocrine treatment, Akt, PKB, erbB-2, hergulin ß1
    Nationell ämneskategori
    Cancer och onkologi
    Identifikatorer
    urn:nbn:se:liu:diva-15031 (URN)10.1038/sj.bjc.6600126 (DOI)
    Tillgänglig från: 2008-10-10 Skapad: 2008-10-10 Senast uppdaterad: 2017-12-11
    2. Cytoplasmic p21WAF1/CIP1 correlates with Akt activation and poor response to tamoxifen in breast cancer
    Öppna denna publikation i ny flik eller fönster >>Cytoplasmic p21WAF1/CIP1 correlates with Akt activation and poor response to tamoxifen in breast cancer
    Visa övriga...
    2006 (Engelska)Ingår i: International Journal of Oncology, ISSN 1019-6439, E-ISSN 1791-2423, Vol. 28, nr 5, s. 1031-1042Artikel i tidskrift (Refereegranskat) Published
    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.

    Nyckelord
    PI3K, heregulin ß1, cell cycle, cell survival
    Nationell ämneskategori
    Cancer och onkologi
    Identifikatorer
    urn:nbn:se:liu:diva-15032 (URN)16596219 (PubMedID)
    Tillgänglig från: 2008-10-10 Skapad: 2008-10-10 Senast uppdaterad: 2020-12-17Bibliografiskt granskad
    3. PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer
    Öppna denna publikation i ny flik eller fönster >>PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer
    Visa övriga...
    2007 (Engelska)Ingår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 13, nr 12, s. 3577-3584Artikel i tidskrift (Refereegranskat) Published
    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.

    Nationell ämneskategori
    Cancer och onkologi
    Identifikatorer
    urn:nbn:se:liu:diva-15041 (URN)10.1158/1078-0432.CCR-06-1609 (DOI)17575221 (PubMedID)
    Tillgänglig från: 2008-10-13 Skapad: 2008-10-13 Senast uppdaterad: 2017-12-11
    4. Clinical Value of RPS6KB1 and RPS6KB2 Gene Amplification in Postmenopausal Breast Cancer
    Öppna denna publikation i ny flik eller fönster >>Clinical Value of RPS6KB1 and RPS6KB2 Gene Amplification in Postmenopausal Breast Cancer
    Visa övriga...
    2008 (Engelska)Artikel i tidskrift (Refereegranskat) Submitted
    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.

    Nyckelord
    PI3K, AKT, mTOR, CCND1, HER2, ER, Tamoxifen
    Nationell ämneskategori
    Cancer och onkologi
    Identifikatorer
    urn:nbn:se:liu:diva-15042 (URN)
    Tillgänglig från: 2008-10-13 Skapad: 2008-10-13 Senast uppdaterad: 2009-04-09
    Ladda ner fulltext (pdf)
    FULLTEXT01
    Ladda ner (pdf)
    COVER01
  • 24.
    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.

  • 25.
    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.

  • 26.
    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, E-ISSN 1791-2423, 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.

  • 27.
    Söderlund Leifler, Karin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Pérez-Tenorio, Gizeh
    Linköpings universitet, Institutionen för biomedicin och kirurgi. 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.
    Activation of the phosphatidylinositol 3-kinase/Akt pathway prevents radiation-induced apoptosis in breast cancer cells2005Ingår i: International Journal of Oncology, ISSN 1019-6439, E-ISSN 1791-2423, Vol. 26, nr 1, s. 25-32Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Radiotherapy is widely used in the treatment of breast cancer and reduces the risk of loco-regional recurrence. Overexpression of the erbB2 receptor occurs in 20-30% of all breast cancers, and seems to be involved in chemotherapeutic resistance of breast cancer cells and radioresistance of lung cancer cells. The hypothesis of this study was that erbB2 confers resistance to radiation-induced apoptosis in breast cancer cells through the phosphatidylinositol 3-kinase (PI3-K)/Akt signalling pathway. Two human breast cancer cell lines were used, BT-474 and MCF-7. BT-474 cells overexpress erbB2 and have mutated p53, while MCF-7 have normal expression of erbB2 and functional p53. The cells were treated with the PI3-K inhibitor wortmannin or the erbB receptor ligand heregulin-ß1, which is expressed by both malignant and stromal cells in vivo. After pharmacological treatment, the cells were irradiated with 10 Gy gamma-radiation. Consistent with the p53 status in the cell lines, gamma-radiation caused G1 arrest in MCF-7 cells, but not in BT-474 cells. 10 Gy gamma-radiation increased apoptosis by on an average 76% (95% CI, 44-109%) in MCF-7. Treatment of MCF-7 with heregulin-ß1 decreased apoptosis by 66% (95% CI, 48-84%) compared to the untreated controls. In BT-474 cells, wortmannin in combination with radiation resulted in 119% (95% CI, 76-161%) more apoptosis compared to wortmannin alone, whereas radiation alone resulted in 45% (95% CI, 15-75%) increased apoptosis. This radiosensitising effect was not seen in MCF-7. Furthermore, transfection of MCF-7 cells with constitutively active Akt made the cells more resistant against apoptosis. Taken together, our results support the hypothesis that the erbB2/PI3-K/Akt signalling pathway is involved in resistance to radiation-induced apoptosis in breast cancer cells in which this signalling pathway is overstimulated.

  • 28.
    Stål, Olle
    et al.
    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.
    Åkerberg, Lind
    Olsson, Birgit
    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.
    Skoog, Lambert
    Division of Cytology, Karolinska Hospital, Stockholm, Sweden .
    Rutqvist, Lars
    Department of Oncology, Huddinge University Hospital, Stockholm, Sweden .
    Akt kinases in breast cancer and the results of adjuvant therapy2003Ingår i: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 5, nr 2, s. R37-R44Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    The serine/threonine kinase Akt, or protein kinase B, has recently been a focus of interest because of its activity to inhibit apoptosis. It mediates cell survival by acting as a transducer of signals from growth factor receptors that activate phosphatidylinositol 3-kinase.

    Methods

    We analysed the expression of the isoforms Akt1 and Akt2 as well as phosphorylated Akt (pAkt) by immunohistochemistry in frozen tumour samples from 280 postmenopausal patients who participated in a randomised trial comparing cyclophosphamide–methotrexate–5-fluorouracil chemotherapy and postoperative radiotherapy. The patients were simultaneously randomised to tamoxifen or to no endocrine treatment.

    Results

    Marked staining was found in 24% of the tumours for Akt1, but in only 4% for Akt2. A low frequency of Akt2-positive cells (1–10%) was observed in another 26% of the tumours. pAkt was significantly associated with both Akt1 and Akt2 expression. Overexpression of erbB2 correlated significantly with pAkt (P = 0.0028). The benefit from tamoxifen was analysed in oestrogen receptor (ER)-positive patients. Patients with a negative status of Akt (no overexpression of Akt1, Akt2 or pAkt) showed significant benefit from tamoxifen. The relative rate of distant recurrence, with versus without tamoxifen, was 0.44 (95% confidence interval [CI], 0.25–0.79) for ER+/Akt1- patients, while it was 0.72 (95% CI, 0.34–1.53) for ER+/Akt1+ patients. The difference in rate ratio did not reach statistical significance. The rate of locoregional recurrence was significantly decreased with radiotherapy versus chemotherapy for Akt-negative patients (rate ratio, 0.23; 95% CI, 0.08–0.67; P = 0.0074), while no benefit was evident for the Akt-positive subgroup (rate ratio, 0.77; 95% CI, 0.31–1.9; P = 0.58). The interaction between Akt and the efficacy of radiotherapy was significant in multivariate analysis (P = 0.042).

    Conclusion

    Activation of the Akt pathway is correlated with erbB2 overexpression in breast cancer. The results suggest that Akt may predict the local control benefit from radiotherapy.

  • 29.
    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

1 - 29 av 29
RefereraExporteraLänk till träfflistan
Permanent länk
Referera
Referensformat
  • apa
  • 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