title: Genome-wide identification of direct target genes implicates estrogen-related receptor alpha as a determinant of breast cancer heterogeneity.
abstract: Estrogen-related receptor alpha (ERRalpha) is an orphan nuclear receptor, the expression of which correlates with negative prognosis in breast cancer. ERRalpha shares functional features with the estrogen receptor alpha (ERalpha) and its activity is modulated by the ERBB2 signaling pathway. Using genome-wide binding sites location analyses in ERalpha-positive and ERalpha-negative breast cancer cell lines, we show that ERRalpha and ERalpha display strict binding site specificity and maintain independent mechanisms of transcriptional activation. Nonetheless, ERRalpha and ERalpha 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 ERRalpha signaling in breast cancer cells is mostly independent of ERalpha, the small fraction of common ERRalpha/ERalpha 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 ERRalpha 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 ERRalpha transcriptional network implicate ERRalpha signaling as a determinant of breast cancer heterogeneity.
authors.affiliation: Rosalind and Morris Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Deblois
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Hall
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Perry
authors.forename: Josée
authors.initials: J
authors.lastname: Laganière
authors.forename: Majid
authors.initials: M
authors.lastname: Ghahremani
authors.forename: Morag
authors.initials: M
authors.lastname: Park
authors.forename: Michael
authors.initials: M
authors.lastname: Hallett
authors.forename: Vincent
authors.initials: V
authors.lastname: Giguère
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004273:DNA, Neoplasm / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011401:Promoter Regions, Genetic; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D004273:DNA, Neoplasm; D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor