Loss of TGF beta Receptor Type 2 Expression Impairs Estrogen Response and Confers Tamoxifen Resistance

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Busch, SusannGothenburg University, Sweden (author)

Loss of TGF beta Receptor Type 2 Expression Impairs Estrogen Response and Confers Tamoxifen Resistance

Article/chapterEnglish2015

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American Association for Cancer Research,2015
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LIBRIS-ID:oai:DiVA.org:liu-117366
https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-117366URI
https://doi.org/10.1158/0008-5472.CAN-14-1583DOI
https://lup.lub.lu.se/record/5277774URI

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Language:English
Summary in:English

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

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Cancer och onkologi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Cancer and Oncology hsv//eng

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Sims, Andrew H.University of Edinburgh, Scotland (author)
Stål, OlleLinköpings universitet,Avdelningen för kliniska vetenskaper,Hälsouniversitetet,Region Östergötland, Onkologiska kliniken US(Swepub:liu)ollst87 (author)
Fernö, MårtenLund University,Lunds universitet,Bröstcancer-genetik,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Breastcancer-genetics,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,Lund University, Sweden(Swepub:lu)onk-mfe (author)
Landberg, GoranGothenburg University, Sweden; University of Manchester, England (author)
Gothenburg University, SwedenUniversity of Edinburgh, Scotland (creator_code:org_t)

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In:Cancer Research: American Association for Cancer Research75:7, s. 1457-14690008-54721538-7445

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By the author/editor: Busch, Susann; Sims, Andrew H.; Stål, Olle; Fernö, Mårten; Landberg, Goran

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Cancer and Oncol ...

Articles in the publication: Cancer Research

By the university: Linköping University; Lund University

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