Genome-wide activity of unliganded Estrogen Receptor alpha in breast cancer cells [ChIP-Seq]

Estrogen Receptor a (ERa) has central role in hormone-dependent breast cancer and its ligand-induced functions have been extensively characterized. However, evidence exists that ERa has functions which are independent of ligands. In the present work, we investigated the binding of ERa to chromatin in absence of ligands, and its function(s) on gene regulation. We demonstrated that in MCF7 breast cancer cells unliganded ERa binds to more than four thousands chromatin sites. Unexpectedly, although almost entirely comprised in the larger group of estrogen-induced binding sites, we found that unliganded-ERa binding is specifically linked to genes with developmental functions, as compared to estrogen-induced binding. Moreover, we found that siRNA-mediated downregulation of ERa in absence of estrogen is accompanied by changes in the expression levels of hundreds of coding and noncoding RNAs. Downregulated mRNAs showed enrichment in genes related to epithelial cell growth and development. Stable ERa downregulation using shRNA, which caused cell-growth arrest, was accompanied by increased H3K27me3 at ERa binding sites. Finally, we found that FOXA1 and AP2? binding to several sites is decreased upon ERa silencing, suggesting that unliganded ERa participates, together with other factors, to the maintenance of the luminal-specific cistrome in breast cancer cells. Overall design: Examination of unliganded estrogen receptor alpha (ERa) DNA interactions in control and ERa siRNA treated MCF7 cells.