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Stål, Olle
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Publications (10 of 122) Show all publications
Blockhuys, S., Celauro, E., Hildesjö, C., Feizi, A., Stål, O., Fierro-González, J. & Wittung-Stafshede, P. (2017). Defining the human copper proteome and analysis of its expression variation in cancers.. Metallomics : integrated biometal science, 9(2), 112-123
Open this publication in new window or tab >>Defining the human copper proteome and analysis of its expression variation in cancers.
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2017 (English)In: Metallomics : integrated biometal science, ISSN 1756-591X, Vol. 9, no 2, p. 112-123Article in journal (Refereed) Published
Abstract [en]

Copper (Cu) is essential for living organisms, and acts as a cofactor in many metabolic enzymes. To avoid the toxicity of free Cu, organisms have specific transport systems that 'chaperone' the metal to targets. Cancer progression is associated with increased cellular Cu concentrations, whereby proliferative immortality, angiogenesis and metastasis are cancer hallmarks with defined requirements for Cu. The aim of this study is to gather all known Cu-binding proteins and reveal their putative involvement in cancers using the available database resources of RNA transcript levels. Using the database along with manual curation, we identified a total of 54 Cu-binding proteins (named the human Cu proteome). Next, we retrieved RNA expression levels in cancer versus normal tissues from the TCGA database for the human Cu proteome in 18 cancer types, and noted an intricate pattern of up- and downregulation of the genes in different cancers. Hierarchical clustering in combination with bioinformatics and functional genomics analyses allowed for the prediction of cancer-related Cu-binding proteins; these were specifically inspected for the breast cancer data. Finally, for the Cu chaperone ATOX1, which is the only Cu-binding protein proposed to have transcription factor activities, we validated its predicted over-expression in patient breast cancer tissue at the protein level. This collection of Cu-binding proteins, with RNA expression patterns in different cancers, will serve as an excellent resource for mechanistic-molecular studies of Cu-dependent processes in cancer.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2017
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-135375 (URN)10.1039/c6mt00202a (DOI)000397437300002 ()27942658 (PubMedID)
Note

Funding agencies: Swedish Society for Medical Research; Folke and Marianne Edler Research Fund; Lars Hierta Memorial Foundation; Knut and Alice Wallenberg Foundation; Swedish Research Council; Chalmers Foundation; NBIS (National Bioinformatics Infrastructure Sweden)

Available from: 2017-03-14 Created: 2017-03-14 Last updated: 2018-05-03Bibliographically approved
Ehinger, A., Malmstrom, P., Bendahl, P.-O., Elston, C. W., Falck, A.-K., Forsare, C., . . . Ferno, M. (2017). Histological grade provides significant prognostic information in addition to breast cancer subtypes defined according to St Gallen 2013. Acta Oncologica, 56(1), 68-74
Open this publication in new window or tab >>Histological grade provides significant prognostic information in addition to breast cancer subtypes defined according to St Gallen 2013
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2017 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, no 1, p. 68-74Article in journal (Refereed) Published
Abstract [en]

Background: The St Gallen surrogate definition of the intrinsic subtypes of breast cancer consist of five subgroups based on estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor type 2 (HER2), and Ki-67. PgR and Ki-67 are used for discriminating between the Luminal A-like and Luminal B-like (HER2-negative) subtypes. Histological grade (G) has prognostic value in breast cancer; however, its relationship to the St Gallen subtypes is not clear. Based on a previous pilot study, we hypothesized that G could be a primary discriminator for ER-positive/HER2-negative breast cancers that were G1 or G3, whereas Ki-67 and PgR could provide additional prognostic information specifically for patients with G2 tumors. To test this hypothesis, a larger patient cohort was examined. Patients and methods: Six hundred seventy-one patients (amp;gt;= 35 years of age, pT1-2, pN0-1) with ER-positive/HER2-negative breast cancer and complete data for PgR, Ki-67, G, lymph node status, tumor size, age, and distant disease-free survival (DDFS; median follow-up 9.2 years) were included. Results: Luminal A-like tumors were mostly G1 or G2 (90%) whereas Luminal B-like tumors were mostly G2 or G3 (87%) and corresponded with good and poor DDFS, respectively. In Luminal B-like tumors that were G1 (n = 23), no metastasis occurred, whereas 14 of 40 Luminal A-like tumors that were G3 metastasized. In the G2 subgroup, low PgR and high Ki-67 were associated with an increased risk of distant metastases, hazard ratio (HR) and 95% confidence interval (CI) 1.8 (0.95-3.4) and 1.5 (0.80-2.8), respectively. Conclusions: Patients with ER-positive/HER2-negative/G1 breast cancer have a good prognosis, similar to that of Luminal A-like, while those with ER-positive/HER2-negative/G3 breast cancer have a worse prognosis, similar to that of Luminal B-like, when assessed independently of PgR and Ki-67. Therapy decisions based on Ki-67 and PgR might thus be restricted to the subgroup G2.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2017
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-134987 (URN)10.1080/0284186X.2016.1237778 (DOI)000392819600011 ()27762648 (PubMedID)
Note

Funding Agencies|Swedish Cancer Society; Gunnar Nilsson Cancer Foundation; Mrs. Berta Kamprad Foundation; Anna and Edwin Bergers Foundation; Swedish Breast Cancer Association (BRO); Swedish Cancer and Allergy Foundation; Scientific Committee of Blekinge County Council; Skane County Councils Research and Development Foundation; Governmental Funding of Clinical Research within the National Health Service

Available from: 2017-03-06 Created: 2017-03-06 Last updated: 2018-05-03
Hilborn, E., Gacic, J., Fornander, T., Nordenskjöld, B., Stål, O. & Jansson, A. (2016). Androgen receptor expression predicts beneficial tamoxifen response in oestrogen receptor-alpha-negative breast cancer. British Journal of Cancer, 114(3), 248-255
Open this publication in new window or tab >>Androgen receptor expression predicts beneficial tamoxifen response in oestrogen receptor-alpha-negative breast cancer
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2016 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 114, no 3, p. 248-255Article in journal (Refereed) Published
Abstract [en]

Background: Although the androgen receptor (AR) is frequently expressed in breast cancer, its relevance in the disease is not fully understood. In addition, the relevance of AR in determining tamoxifen treatment efficiency requires evaluation. Purpose: To investigate the tamoxifen predictive relevance of the AR protein expression in breast cancer. Methods Patients were randomised to tamoxifen 40 mg daily for 2 or 5 years or to no endocrine treatment. Mean follow-up was 15 years. Hazard ratios were calculated with recurrence-free survival as end point. Results: In patients with oestrogen receptor (ER)-negative tumours, expression of AR predicted decreased recurrence rate with tamoxifen (hazard ratio (HR) = 0.34; 95% confidence interval (CI) = 0.14-0.81; P = 0.015), whereas the opposite was seen in the AR- group (HR = 2.92; 95% CI = 1.16-7.31; P = 0.022). Interaction test was significant P < 0.001. Patients with triple-negative and AR+ tumours benefitted from tamoxifen treatment (HR = 0.12; 95% CI = 0.014-0.95 P = 0.044), whereas patients with AR- tumours had worse outcome when treated with tamoxifen (HR = 3.98; 95% CI = 1.32-12.03; P = 0.014). Interaction test was significant P = 0.003. Patients with ER+ tumours showed benefit from tamoxifen treatment regardless of AR expression. Conclusions: AR can predict tamoxifen treatment benefit in patients with ER- tumours and triple-negative breast cancer.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2016
Keywords
Androgen receptor; breast cancer; tamoxifen; oestrogen receptor; triple-negative breast cancer
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-125675 (URN)10.1038/bjc.2015.464 (DOI)000369223600003 ()26742006 (PubMedID)
Note

Funding Agencies|Swedish research council [A0346701]; Swedish cancer foundation [13 0435]

Available from: 2016-03-02 Created: 2016-02-29 Last updated: 2017-05-03
Manna, S., Bostner, J., Sun, Y., Miller, L. D., Alayev, A., Schwartz, N. S., . . . Holz, M. K. (2016). ERRα Is a Marker of Tamoxifen Response and Survival in Triple-Negative Breast Cancer.. Clinical Cancer Research, 22(6), 1421-1431
Open this publication in new window or tab >>ERRα Is a Marker of Tamoxifen Response and Survival in Triple-Negative Breast Cancer.
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2016 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 22, no 6, p. 1421-1431Article in journal (Refereed) Published
Abstract [en]

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

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

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

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

Place, publisher, year, edition, pages
AMER ASSOC CANCER RESEARCH, 2016
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-125928 (URN)10.1158/1078-0432.CCR-15-0857 (DOI)000373358900018 ()26542058 (PubMedID)
Note

Funding agencies:  NIH [CA151112, HL098216]; Atol Charitable Trust; American Cancer Society [RSG-13-287-01-TBE]; National Cancer Center; Yeshiva University; Swedish Cancer Society

Available from: 2016-03-09 Created: 2016-03-09 Last updated: 2018-03-21
Veenstra, C., Perez-Tenorio, G., Stelling, A., Karlsson, E., Mirwani Mirwani, S., Nordenskjöld, B., . . . Stål, O. (2016). Met and its ligand HGF are associated with clinical outcome in breast cancer. OncoTarget, 7(24), 37145-37159
Open this publication in new window or tab >>Met and its ligand HGF are associated with clinical outcome in breast cancer
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 24, p. 37145-37159Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
IMPACT JOURNALS LLC, 2016
Keywords
radiation; copy number variation; droplet digital PCR; triple-negative breast cancer; radiotherapy
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-130130 (URN)10.18632/oncotarget.9268 (DOI)000377756800127 ()27175600 (PubMedID)
Note

Funding Agencies|Swedish Cancer Society; Swedish Research Council; LiU Cancer Foundation

Available from: 2016-07-12 Created: 2016-07-11 Last updated: 2018-03-23
Gabrielson, M., Reizer, E., Stål, O. & Tina, E. (2016). Mitochondrial regulation of cell cycle progression through SLC25A43. Biochemical and Biophysical Research Communications - BBRC, 469(4), 1090-1096
Open this publication in new window or tab >>Mitochondrial regulation of cell cycle progression through SLC25A43
2016 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 469, no 4, p. 1090-1096Article in journal (Refereed) Published
Abstract [en]

An increasing body of evidence is pointing towards mitochondrial regulation of the cell cycle. In a previous study of HER2-positive tumours we could demonstrate a common loss in the gene encoding for the mitochondrial transporter SLC25A43 and also a significant relation between SLC25A43 protein expression and S-phase fraction. Here, we investigated the consequence of suppressed SLC25A43 expression on cell cycle progression and proliferation in breast epithelial cells. In the present study, we suppressed SLC25A43 using siRNA in immortalised non-cancerous breast epithelial MCF10A cells and HER2-positive breast cancer cells BT-474. Viability, apoptosis, cell proliferation rate, cell cycle phase distribution, and nuclear Ki-67 and p21, were assessed by flow cytometry. Cell cycle related gene expressions were analysed using real-time PCR. We found that SLC25A43 knockdown in MCF10A cells significantly inhibited cell cycle progression during G(1)-to-S transition, thus significantly reducing the proliferation rate and fraction of Ki-67 positive MCF10A cells. In contrast, suppressed SLC25A43 expression in BT-474 cells resulted in a significantly increased proliferation rate together with an enhanced G(1)-to-S transition. This was reflected by an increased fraction of Ki-67 positive cells and reduced level of nuclear p21. In line with our previous results, we show a role for SLC25A43 as a regulator of cell cycle progression and proliferation through a putative mitochondrial checkpoint. These novel data further strengthen the connection between mitochondrial function and the cell cycle, both in non-malignant and in cancer cells. (C) 2015 Elsevier Inc. All rights reserved.

Place, publisher, year, edition, pages
ACADEMIC PRESS INC ELSEVIER SCIENCE, 2016
Keywords
SLC25A43; Mitochondrial checkpoint; Proliferation; Cell cycle regulation; Ki-67
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-125685 (URN)10.1016/j.bbrc.2015.12.088 (DOI)000369353000046 ()26721434 (PubMedID)
Note

Funding Agencies|Lion Cancer Foundation Sweden; Research Committee at Orebro County Council; Swedish Research Council [K2011-54X-20639-04-6]

Available from: 2016-03-01 Created: 2016-02-29 Last updated: 2017-11-30
Ekholm, M., Bendahl, P.-O., Ferno, M., Nordenskjöld, B., Stål, O. & Ryden, L. (2016). Two Years of Adjuvant Tamoxifen Provides a Survival Benefit Compared With No Systemic Treatment in Premenopausal Patients With Primary Breast Cancer: Long-Term Follow-Up (> 25 years) of the Phase III SBII:2pre Trial. Journal of Clinical Oncology, 34(19), 2232-+
Open this publication in new window or tab >>Two Years of Adjuvant Tamoxifen Provides a Survival Benefit Compared With No Systemic Treatment in Premenopausal Patients With Primary Breast Cancer: Long-Term Follow-Up (> 25 years) of the Phase III SBII:2pre Trial
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2016 (English)In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 34, no 19, p. 2232-+Article in journal (Refereed) Published
Abstract [en]

Purpose The aim of this study was to evaluate the long-term effect of 2 years of adjuvant tamoxifen compared with no systemic treatment (control) in premenopausal patients with breast cancer over different time periods through long-term (amp;gt; 25 years) follow-up. Patients and Methods Premenopausal patients with primary breast cancer (N = 564) were randomly assigned to 2 years of tamoxifen (n = 276) or no systemic treatment (n = 288). Data regarding date and cause of death were obtained from the Swedish Cause of Death Register. End points were cumulative mortality (CM) and cumulative breast cancer-related mortality (CBCM). The median follow-up for the 250 patients still alive in April 2014 was 26.3 years (range, 22.7 to 29.7 years). Results In patients with estrogen receptor-positive tumors (n = 362), tamoxifen was associated with a marginal reduction in CM (hazard ratio [HR], 0.77; 95% CI, 0.58 to 1.03; P = .075) and a significant reduction in CBCM (HR, 0.73; 95% CI, 0.53 to 0.99; P = .046). The effect seemed to vary over time (CM years 0 to 5: HR, 1.05; 95% CI, 0.64 to 1.73; years amp;gt;5 to 15: HR, 0.58; 95% CI, 0.37 to 0.91; and after 15 years: HR, 0.82; 95% CI, 0.48 to 1.42; CBCM years 0 to 5: HR, 1.09; 95% CI, 0.65 to 1.82; years amp;gt;5 to 15: HR, 0.53; 95% CI, 0.33 to 0.86; and after 15 years: HR, 0.72; 95% CI, 0.36 to 1.44). Conclusion Two years of adjuvant tamoxifen resulted in a long-term survival benefit in premenopausal patients with estrogen receptor-positive primary breast cancer. (C) 2016 by American Society of Clinical Oncology. Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: https://creativecommons.org/licenses/by-nc-nd/4.0/

Place, publisher, year, edition, pages
AMER SOC CLINICAL ONCOLOGY, 2016
National Category
Surgery
Identifiers
urn:nbn:se:liu:diva-130273 (URN)10.1200/JCO.2015.65.6272 (DOI)000378647000006 ()27161974 (PubMedID)
Available from: 2016-08-01 Created: 2016-07-28 Last updated: 2017-11-28
Gothlin Eremo, A., Tina, E., Wegman, P., Stål, O., Fransen, K., Fornander, T. & Wingren, S. (2015). HER4 tumor expression in breast cancer patients randomized to treatment with or without tamoxifen. International Journal of Oncology, 47(4), 1311-1320
Open this publication in new window or tab >>HER4 tumor expression in breast cancer patients randomized to treatment with or without tamoxifen
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2015 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 47, no 4, p. 1311-1320Article in journal (Refereed) Published
Abstract [en]

The human epidermal growth factor receptor (HER) 4 is a relative of HER2 and has been associated to endocrine breast cancer and prediction of tamoxifen response. In addition to PI3K/Akt and MAPK pathway activation, ligand binding to HER4 triggers proteolytic cleavage and release of an intracellular receptor domain (4ICD) with signaling properties. The aim of the present study was to analyze HER4 protein expression and intracellular localization in breast cancer tissue from patients randomized to treatment with or without adjuvant tamoxifen. To investigate HER4 expression and localization in response to estradiol (E2) and 4-hydroxytamoxifen (4-OHT) exposure, we also performed in vitro studies. Cytoplasmic, nuclear and membrane expression of HER4 protein was evaluated by immunohistochemical staining in tumor tissue from 912 breast cancer patients. Three different breast epithelia cancer cell lines were exposed to E2 and 4-OHT and mRNA expression was analyzed using qPCR. Further, nuclear and cytoplasmic proteins were separated and analyzed with western blotting. We found an association between nuclear HER4 protein expression and ER-positivity (P=0.004). Furthermore, significant association was found between cytoplasmic HER4 and ER-negativity (Pless than0.0005), PgR-negativity (Pless than0.0005), tumor size greater than20 mm (P=0.001) and HER2-negativity (P=0.008). However, no overall significance of HER4 on recurrence-free survival was found. After E2 exposure, HER4 mRNA and protein expression had decreased in two cell lines in vitro yet no changes in nuclear or cytoplasmic protein fractions were seen. In conclusion, nuclear HER4 seem to be co-located with ER, however, we did not find support for overall HER4 expression in independently predicting response of tamoxifen treatment. The possible influence of separate isoforms was not tested and future studies may further evaluate HER4 significance.

Place, publisher, year, edition, pages
SPANDIDOS PUBL LTD, 2015
Keywords
breast cancer; ErbB4; HER4; randomized patients; tamoxifen
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-122207 (URN)10.3892/ijo.2015.3108 (DOI)000362058300015 ()26238412 (PubMedID)
Note

Funding Agencies|Nyckelfonden, Orebro University Hospital, Sweden; Lions Cancer Research Foundation, Region Uppsala - Orebro, Sweden; Stockholm Cancer Society, Sweden

Available from: 2015-10-26 Created: 2015-10-23 Last updated: 2017-12-01
Karlsson, E., Veenstra, C., Emin, S., Dutta, C., Perez-Tenorio, G., Nordenskjöld, B., . . . Stål, O. (2015). Loss of protein tyrosine phosphatase, non-receptor type 2 is associated with activation of AKT and tamoxifen resistance in breast cancer. Breast Cancer Research and Treatment, 153(1), 31-40
Open this publication in new window or tab >>Loss of protein tyrosine phosphatase, non-receptor type 2 is associated with activation of AKT and tamoxifen resistance in breast cancer
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2015 (English)In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 153, no 1, p. 31-40Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Springer Verlag (Germany), 2015
Keywords
18p; AKT; Breast cancer; Endocrine resistance; Phosphatases; PTPN2
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-121133 (URN)10.1007/s10549-015-3516-y (DOI)000359775100005 ()26208487 (PubMedID)
Note

Funding Agencies|Swedish Cancer Society [13 0435]; Swedish Research Council [A0346701]

Available from: 2015-09-08 Created: 2015-09-08 Last updated: 2017-12-04
Busch, S., Sims, A. H., Stål, O., Ferno, M. & Landberg, G. (2015). Loss of TGF beta Receptor Type 2 Expression Impairs Estrogen Response and Confers Tamoxifen Resistance. Cancer Research, 75(7), 1457-1469
Open this publication in new window or tab >>Loss of TGF beta Receptor Type 2 Expression Impairs Estrogen Response and Confers Tamoxifen Resistance
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2015 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 7, p. 1457-1469Article in journal (Refereed) Published
Abstract [en]

One third of the patients with estrogen receptor alpha (ER alpha)-positive breast cancer who are treated with the antiestrogen tamoxifen will either not respond to initial therapy or will develop drug resistance. Endocrine response involves crosstalk between ER alpha and TGF beta signaling, such that tamoxifen non-responsiveness or resistance in breast cancer might involve aberrant TGF beta signaling. In this study, we analyzed TGF beta receptor type 2 (TGFBR2) expression and correlated it with ER alpha status and phosphorylation in a cohort of 564 patients who had been randomized to tamoxifen or no-adjuvant treatment for invasive breast carcinoma. We also evaluated an additional four independent genetic datasets in invasive breast cancer. In all the cohorts we analyzed, we documented an association of low TGFBR2 protein and mRNA expression with tamoxifen resistance. Functional investigations confirmed that cell cycle or apoptosis responses to estrogen or tamoxifen in ER alpha-positive breast cancer cells were impaired by TGFBR2 silencing, as was ER alpha phosphorylation, tamoxifen-induced transcriptional activation of TGF beta, and upregulation of the multidrug resistance protein ABCG2. Acquisition of low TGFBR2 expression as a contributing factor to endocrine resistance was validated prospectively in a tamoxifen-resistant cell line generated by long-term drug treatment. Collectively, our results established a central contribution of TGF beta signaling in endocrine resistance in breast cancer and offered evidence that TGFBR2 can serve as an independent biomarker to predict treatment outcomes in ER alpha-positive forms of this disease.

Place, publisher, year, edition, pages
American Association for Cancer Research, 2015
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-117366 (URN)10.1158/0008-5472.CAN-14-1583 (DOI)000351948900031 ()25833830 (PubMedID)
Note

Funding Agencies|Swedish Cancer Society; Breakthrough Breast Cancer UK; BioCARE-a National Strategic Research Program at University of Gothenburg

Available from: 2015-04-24 Created: 2015-04-24 Last updated: 2017-12-04
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