Global analysis of estrogen receptor beta binding to breast cancer cell genome reveals an extensive interplay with estrogen receptor alpha for target gene regulation.

ABSTRACT: BACKGROUND: Estrogen receptors alpha (ER?) and beta (ER?) 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 ER? being able to modulate the effects of ER? on gene transcription and cell proliferation. ER? is frequently lost in BC, where its presence generally correlates with a better prognosis of the disease. The identification of the genomic targets of ER? 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 ER? in hormone-responsive, ER?-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 ER? and 6024 ER? binding sites in estrogen-stimulated cells, comprising sites occupied by either ER?, ER? 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 ER?+ vs ER?- cells, 424 showed one or more ER? site within 10 kb. These putative primary ER? 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. ER? 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 ER? can bind also ER?, suggesting that the overall action of ER? on the genome of hormone-responsive BC cells depends mainly on the relative concentration of both ERs in the cell.

SUBMITTER: Grober OM 

PROVIDER: S-EPMC3025958 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature