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

¹ Rosalind and Morris Goodman Cancer Centre; ² Department of Biochemistry, ³ McGill Centre for Bioinformatics, and Departments of ⁴ Medicine and ⁵ Oncology, McGill University, Montreal, Quebec, Canada

Requests for reprints: Vincent Giguère, Rosalind and Morris Goodman Cancer Centre, McGill University, 1160 Pine Avenue West, Montreal, Quebec, Canada H3A 1A3. Phone: 514-398-5899; Fax: 514-398-6769; E-mail: vincent.giguere{at}mcgill.ca.

Key Words: chromatin immunoprecipitation • ERBB2 • estrogen receptor • genome wide • transcription

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