title: Genome-wide activity of unliganded estrogen receptor-α in breast cancer cells.
abstract: Estrogen receptor-α (ERα) has central role in hormone-dependent breast cancer and its ligand-induced functions have been extensively characterized. However, evidence exists that ERα has functions that are independent of ligands. In the present work, we investigated the binding of ERα to chromatin in the absence of ligands and its functions on gene regulation. We demonstrated that in MCF7 breast cancer cells unliganded ERα 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-ERα binding is specifically linked to genes with developmental functions, compared with estrogen-induced binding. Moreover, we found that siRNA-mediated down-regulation of ERα 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 ERα down-regulation using shRNA, which caused cell growth arrest, was accompanied by increased H3K27me3 at ERα binding sites. Finally, we found that FOXA1 and AP2γ binding to several sites is decreased upon ERα silencing, suggesting that unliganded ERα participates, together with other factors, in the maintenance of the luminal-specific cistrome in breast cancer cells.
authors.affiliation: Center for Molecular Systems Biology, University of Turin, 10043 Orbassano, Turin, Italy.
authors.forename: Livia
authors.initials: L
authors.lastname: Caizzi
authors.forename: Giulio
authors.initials: G
authors.lastname: Ferrero
authors.forename: Santina
authors.initials: S
authors.lastname: Cutrupi
authors.forename: Francesca
authors.initials: F
authors.lastname: Cordero
authors.forename: Cecilia
authors.initials: C
authors.lastname: Ballaré
authors.forename: Valentina
authors.initials: V
authors.lastname: Miano
authors.forename: Stefania
authors.initials: S
authors.lastname: Reineri
authors.forename: Laura
authors.initials: L
authors.lastname: Ricci
authors.forename: Olivier
authors.initials: O
authors.lastname: Friard
authors.forename: Alessandro
authors.initials: A
authors.lastname: Testori
authors.forename: Davide
authors.initials: D
authors.lastname: Corà
authors.forename: Michele
authors.initials: M
authors.lastname: Caselle
authors.forename: Luciano
authors.initials: L
authors.lastname: Di Croce
authors.forename: Michele
authors.initials: M
authors.lastname: De Bortoli
mesh_terms: D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D063990:Gene Ontology; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D008024:Ligands; D061986:MCF-7 Cells; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D008024:Ligands; D034741:RNA, Small Interfering
keywords: chromatin binding; enhancer; epigenetics; pioneer factors; transcriptome