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Global analysis of estrogen receptor beta binding to breast cancer cell genome reveals an extensive interplay with estrogen receptor alpha for target gene regulation.
BMC Genomics. 2011 Jan 14;12(1):36
Authors: Grober OM, Mutarelli M, Giurato G, Ravo M, Cicatiello L, De Filippo MR, Ferraro L, Nassa G, Papa MF, Paris O, Tarallo R, Luo S, Schroth GP, Benes V, Weisz A
ABSTRACT: BACKGROUND: Estrogen receptors alpha (ERalpha) and beta (ERbeta) are transcription factors (TFs) that mediate estrogen signaling and define the hormone-responsive phenotype of breast cancer (BC). The two receptors can be found co-expressed and play specific, often opposite, roles, with ERbeta being able to modulate the effects of ERalpha on gene transcription and cell proliferation. ERbeta is frequently lost in BC, where its presence generally correlates with a better prognosis of the disease. The identification of the genomic targets of ERbeta in hormone-responsive BC cells is thus a critical step to elucidate the roles of this receptor in estrogen signaling and tumor cell biology. RESULTS: Expression of full-length ERbeta in hormone-responsive, ERalpha-positive MCF-7 cells resulted in a marked reduction in cell proliferation in response to estrogen and marked effects on the cell transcriptome. By ChIP-Seq we identified 9702 ERbeta and 6024 ERalpha binding sites in estrogen-stimulated cells, comprising sites occupied by either ERbeta, ERalpha or both ER subtypes. A search for TF binding matrices revealed that the majority of the binding sites identified comprise one or more Estrogen Response Element and the remaining show binding matrixes for other TFs known to mediate ER interaction with chromatin by tethering, including AP2, E2F and SP1. Of 921 genes differentially regulated by estrogen in ERbeta+ vs ERbeta- cells, 424 showed one or more ERbeta site within 10 kb. These putative primary ERbeta target genes control cell proliferation, death, differentiation, motility and adhesion, signal transduction and transcription, key cellular processes that might explain the biological and clinical phenotype of tumors expressing this ER subtype. ERbeta binding in close proximity of several miRNA genes and in the mitochondrial genome, suggests the possible involvement of this receptor in small non-coding RNA biogenesis and mitochondrial genome functions. CONCLUSIONS: Results indicate that the vast majority of the genomic targets of ERbeta can bind also ERalpha, suggesting that the overall action of ERbeta on the genome of hormone-responsive BC cells depends mainly on the relative concentration of both ERs in the cell.
PMID: 21235772 [PubMed - as supplied by publisher]
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Global analysis of estrogen receptor beta binding to breast cancer cell genome reveals an extensive interplay with estrogen receptor alpha for target gene regulation.
BMC Genomics. 2011 Jan 14;12(1):36
Authors: Grober OM, Mutarelli M, Giurato G, Ravo M, Cicatiello L, De Filippo MR, Ferraro L, Nassa G, Papa MF, Paris O, Tarallo R, Luo S, Schroth GP, Benes V, Weisz A
ABSTRACT: BACKGROUND: Estrogen receptors alpha (ERalpha) and beta (ERbeta) are transcription factors (TFs) that mediate estrogen signaling and define the hormone-responsive phenotype of breast cancer (BC). The two receptors can be found co-expressed and play specific, often opposite, roles, with ERbeta being able to modulate the effects of ERalpha on gene transcription and cell proliferation. ERbeta is frequently lost in BC, where its presence generally correlates with a better prognosis of the disease. The identification of the genomic targets of ERbeta in hormone-responsive BC cells is thus a critical step to elucidate the roles of this receptor in estrogen signaling and tumor cell biology. RESULTS: Expression of full-length ERbeta in hormone-responsive, ERalpha-positive MCF-7 cells resulted in a marked reduction in cell proliferation in response to estrogen and marked effects on the cell transcriptome. By ChIP-Seq we identified 9702 ERbeta and 6024 ERalpha binding sites in estrogen-stimulated cells, comprising sites occupied by either ERbeta, ERalpha or both ER subtypes. A search for TF binding matrices revealed that the majority of the binding sites identified comprise one or more Estrogen Response Element and the remaining show binding matrixes for other TFs known to mediate ER interaction with chromatin by tethering, including AP2, E2F and SP1. Of 921 genes differentially regulated by estrogen in ERbeta+ vs ERbeta- cells, 424 showed one or more ERbeta site within 10 kb. These putative primary ERbeta target genes control cell proliferation, death, differentiation, motility and adhesion, signal transduction and transcription, key cellular processes that might explain the biological and clinical phenotype of tumors expressing this ER subtype. ERbeta binding in close proximity of several miRNA genes and in the mitochondrial genome, suggests the possible involvement of this receptor in small non-coding RNA biogenesis and mitochondrial genome functions. CONCLUSIONS: Results indicate that the vast majority of the genomic targets of ERbeta can bind also ERalpha, suggesting that the overall action of ERbeta on the genome of hormone-responsive BC cells depends mainly on the relative concentration of both ERs in the cell.
PMID: 21235772 [PubMed - as supplied by publisher]
More...