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

Estrogen-related receptor alpha (ERR alpha) is an orphan nuclear receptor, the expression of which correlates with negative prognosis in breast cancer. ERR alpha shares functional features with the estrogen receptor alpha (ER alpha) and its activity is modulated by the ERBB2 signaling pathway. Using genome-wide binding sites location analyses in ER alpha-positive and ER alpha-negative breast cancer cell lines, we show that ERR alpha and ER alpha display strict binding site specificity and maintain independent mechanisms of transcriptional activation. Nonetheless, ERR alpha and ER alpha 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 ERR alpha signaling in breast cancer cells is mostly independent of ER alpha the small fraction of common ERR alpha/ER alpha 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 ERR alpha 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 ERR alpha transcriptional network implicate ERR alpha signaling as a determinant of breast cancer heterogeneity. [Cancer Res 2009;69(15):6149-57]