Loss of TGFß Receptor Type 2 Expression Impairs Estrogen Response and Confers Tamoxifen Resistance.

Cancer Research

PubMedID: 25833830

Busch S, Sims AH, Stål O, Fernö M, Landberg G. Loss of TGFß Receptor Type 2 Expression Impairs Estrogen Response and Confers Tamoxifen Resistance. Cancer Res. 2015;75(7):1457-69.
One third of the patients with estrogen receptor a (ERa)-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 ERa and TGFß signaling, such that tamoxifen nonresponsiveness or resistance in breast cancer might involve aberrant TGFß signaling. In this study, we analyzed TGFß receptor type 2 (TGFBR2) expression and correlated it with ERa 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 ERa-positive breast cancer cells were impaired by TGFBR2 silencing, as was ERa phosphorylation, tamoxifen-induced transcriptional activation of TGFß, 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 TGFß signaling in endocrine resistance in breast cancer and offered evidence that TGFBR2 can serve as an independent biomarker to predict treatment outcomes in ERa-positive forms of this disease. Cancer Res; 75(7); 1457-69. ©2015 AACR.