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Loss of TGF beta Receptor Type 2 Expression Impairs Estrogen Response and Confers Tamoxifen Resistance
Gothenburg University, Sweden.
University of Edinburgh, Scotland.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
Lund University, Sweden.
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2015 (engelsk)Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, nr 7, s. 1457-1469Artikkel i tidsskrift (Fagfellevurdert) 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.

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American Association for Cancer Research , 2015. Vol. 75, nr 7, s. 1457-1469
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URN: urn:nbn:se:liu:diva-117366DOI: 10.1158/0008-5472.CAN-14-1583ISI: 000351948900031PubMedID: 25833830OAI: oai:DiVA.org:liu-117366DiVA, id: diva2:807867
Merknad

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

Tilgjengelig fra: 2015-04-24 Laget: 2015-04-24 Sist oppdatert: 2017-12-04

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