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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.
Highlights
Breast tumor development and progression are complex processes that involve the contribution of numerous signaling pathways, depicting the high degree of heterogeneity of the disease [1]
We examined Estrogen-related receptor a (ERRa) binding sites in the Estrogen receptor a (ERa)-positive MCF-7 human breast cancer cell line cultured in phenol red–free DMEM supplemented with hormonedepleted serum
The identification of ERRa target genes in human breast cancer cells established an unequivocal distinction between ERRa and ERa transcriptional activities at a genomic, functional, and mechanistic levels in breast cancer cells
Summary
Breast tumor development and progression are complex processes that involve the contribution of numerous signaling pathways, depicting the high degree of heterogeneity of the disease [1]. The identification of factors contributing to breast cancer initiation or progression and possessing the potential to modulate both ERa and ERBB2 signaling pathways represents an interesting avenue for the development of more effective and all-encompassing therapies. The expression of ERRa in breast tumors correlates with negative prognosis and positively and inversely correlates with ERBB2 and ERa status, respectively [9, 10]. Taken together, these findings suggest that ERRa could contribute to the biology of several subtypes of breast cancer
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