Genome-Wide Identification of Direct Target Genes Implicates Estrogen-Related Receptor α as a Determinant of Breast Cancer Heterogeneity

Estrogen-related receptor α (ERRα) is an orphan nuclear receptor, the expression of which correlates with negative prognosis in breast cancer. ERRα shares functional features with the estrogen receptor α (ERα) and its activity is modulated by the ERBB2 signaling pathway. Using genome-wide binding sites location analyses in ERα-positive and ERα-negative breast cancer cell lines, we show that ERRα and ERα display strict binding site specificity and maintain independent mechanisms of transcriptional activation. Nonetheless, ERRα and ERα coregulate a small subset of common target genes via binding either to a dual-specificity binding site or to distinct cognate binding sites located within the extended promoter region of the gene. Although ERRα signaling in breast cancer cells is mostly independent of ERα, the small fraction of common ERRα/ERα targets comprises genes with high relevance to breast tumor biology, including genes located within the ERBB2 amplicon and GATA3 . Finally, unsupervised hierarchical clustering based on the expression profiling of ERRα direct target genes in human breast tumors revealed four main clusters that recapitulate established tumor subtypes. Taken together, the identification and functional characterization of the ERRα transcriptional network implicate ERRα signaling as a determinant of breast cancer heterogeneity. [Cancer Res 2009;69(15):6149–57]