Reprogramming of the ERRα and ERα Target Gene Landscape Triggers Tamoxifen Resistance in Breast Cancer

Endocrine treatment regimens for breast cancer that target the estrogen receptor-alpha (ER alpha) are effective, but acquired resistance remains a limiting drawback. One mechanism of acquired resistance that has been hypothesized is functional substitution of the orphan receptor estrogen-related receptor-alpha (ERR alpha) for ER alpha. To examine this hypothesis, we analyzed ERR alpha and ER alpha in recurrent tamoxifen-resistant breast tumors and conducted a genome-wide target gene profiling analysis of MCF-7 breast cancer cell populations that were sensitive or resistant to tamoxifen treatment. This analysis uncovered a global redirection in the target genes controlled by ER alpha, ERR alpha, and their coactivator AIB1, defining a novel set of target genes in tamoxifen-resistant cells. Beyond differences in the ER alpha and ERR alpha target gene repertoires, both factors were engaged in similar pathobiologic processes relevant to acquired resistance. Functional analyses confirmed a requirement for ERR alpha in tamoxifen-and fulvestrant-resistant MCF-7 cells, with pharmacologic inhibition of ERR alpha sufficient to partly restore sensitivity to antiestrogens. In clinical specimens (n - 1041), increased expression of ERR alpha was associated with enhanced proliferation and aggressive disease parameters, including increased levels of p53 in ER alpha-positive cases. In addition, increased ERR alpha expression was linked to reduced overall survival in independent tamoxifen-treated patient cohorts. Taken together, our results suggest that ER alpha and ERR alpha cooperate to promote endocrine resistance, and they provide a rationale for the exploration of ERR alpha as a candidate drug target to treat endocrine-resistant breast cancer. (C)2015 AACR.