Loss of estrogen receptor signaling triggers epigenetic silencing of downstream targets in breast cancer

Yu Wei Leu, Pearlly S. Yan, Meiyun Fan, Victor X. Jin, Joseph C. Liu, Edward M. Curran, Wade V. Welshons, Susan H. Wei, Ramana V. Davuluri, Christoph Plass, Kenneth P. Nephew, Tim H.M. Huang

Research output: Contribution to journalArticlepeer-review

164 Scopus citations

Abstract

Alterations in histones, chromatin-related proteins, and DNA methylation contribute to transcriptional silencing in cancer, but the sequence of these molecular events is not well understood. Here we demonstrate that on disruption of estrogen receptor (ER) α signaling by small interfering RNA, polycomb repressors and histone deacetylases are recruited to initiate stable repression of the progesterone receptor (PR) gene, a known ERα target, in breast cancer cells. The event is accompanied by acquired DNA methylation of the PR promoter, leaving a stable mark that can be inherited by cancer cell progeny. Reestablishing ERa signaling alone was not sufficient to reactivate the PR gene; reactivation of the PR gene also requires DNA demethylation. Methylation microarray analysis further showed that progressive DNA methylation occurs in multiple ERα targets in breast cancer genomes. The results imply, for the first time, the significance of epigenetic regulation on ERα target genes, providing new direction for research in this classical signaling pathway.

Original languageEnglish (US)
Pages (from-to)8184-8192
Number of pages9
JournalCancer Research
Volume64
Issue number22
DOIs
StatePublished - Nov 15 2004

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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