Genome-wide activity of unliganded estrogen receptor-α in breast cancer cells

Livia Caizzi, Giulio Ferrero, Santina Cutrupi, Francesca Cordero, Cecilia Ballaré, Valentina Miano, Stefania Reineri, Laura Ricci, Olivier Friard, Alessandro Testori, Davide Corà, Michele Caselle, Luciano Di Croce, Michele De Bortoli

Research output: Contribution to journalArticlepeer-review

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-regulatedmRNAs 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.

Original languageEnglish
Pages (from-to)4892-4897
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number13
DOIs
Publication statusPublished - Apr 1 2014

Keywords

  • Chromatin binding
  • Enhancer
  • Epigenetics
  • Pioneer factors
  • Transcriptome

ASJC Scopus subject areas

  • General

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