期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：13
页码：4892-4897
DOI：10.1073/pnas.1315445111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Estrogen receptor- (ER) has central role in hormone-dependent breast cancer and its ligand-induced functions have been extensively characterized. However, evidence exists that ER has functions that are independent of ligands. In the present work, we investigated the binding of ER to chromatin in the absence of ligands and its functions on gene regulation. We demonstrated that in MCF7 breast cancer cells unliganded ER binds to more than 4,000 chromatin sites. Unexpectedly, although almost entirely comprised in the larger group of estrogen-induced binding sites, we found that unliganded-ER binding is specifically linked to genes with developmental functions, compared with estrogen-induced binding. Moreover, we found that siRNA-mediated down-regulation of ER in absence of estrogen is accompanied by changes in the expression levels of hundreds of coding and noncoding RNAs. Down-regulated mRNAs showed enrichment in genes related to epithelial cell growth and development. Stable ER down-regulation using shRNA, which caused cell growth arrest, was accompanied by increased H3K27me3 at ER binding sites. Finally, we found that FOXA1 and AP2{gamma} binding to several sites is decreased upon ER silencing, suggesting that unliganded ER participates, together with other factors, in the maintenance of the luminal-specific cistrome in breast cancer cells.
