ERRα Is a Marker of Tamoxifen Response and Survival in Triple-Negative Breast Cancer

Purpose: Estrogen-related receptor alpha (ERR alpha) signaling has recently been implicated in breast cancer. We investigated the clinical value of ERR alpha 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 ERRa 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 ERR alpha. The phenotypic effects associated with ERR alpha 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, ERR alpha expression indicated worse prognosis and correlated with poor outcome predictors. However, in tamoxifen-treated patients, an improved outcome was observed with high ERR alpha gene and protein expression. Reduced ERR alpha expression was oncogenic in the presence of tamoxifen, measured by in vitro proliferation and migration assays and in vivo metastasis studies. Conclusions: Taken together, these data show that ERR alpha expression predicts response to tamoxifen treatment, and ERR alpha could be a biomarker of tamoxifen sensitivity and a prognostic factor in TNBC. (C) 2015 AACR.