A New Role for ERα: Silencing via DNA Methylation of Basal, Stem Cell, and EMT Genes

Mol Cancer Res. 2017 Feb;15(2):152-164. doi: 10.1158/1541-7786.MCR-16-0283. Epub 2016 Nov 15.


Resistance to hormonal therapies is a major clinical problem in the treatment of estrogen receptor α-positive (ERα+) breast cancers. Epigenetic marks, namely DNA methylation of cytosine at specific CpG sites (5mCpG), are frequently associated with ERα+ status in human breast cancers. Therefore, ERα may regulate gene expression in part via DNA methylation. This hypothesis was evaluated using a panel of breast cancer cell line models of antiestrogen resistance. Microarray gene expression profiling was used to identify genes normally silenced in ERα+ cells but derepressed upon exposure to the demethylating agent decitabine, derepressed upon long-term loss of ERα expression, and resuppressed by gain of ERα activity/expression. ERα-dependent DNA methylation targets (n = 39) were enriched for ERα-binding sites, basal-up/luminal-down markers, cancer stem cell, epithelial-mesenchymal transition, and inflammatory and tumor suppressor genes. Kaplan-Meier survival curve and Cox proportional hazards regression analyses indicated that these targets predicted poor distant metastasis-free survival among a large cohort of breast cancer patients. The basal breast cancer subtype markers LCN2 and IFI27 showed the greatest inverse relationship with ERα expression/activity and contain ERα-binding sites. Thus, genes that are methylated in an ERα-dependent manner may serve as predictive biomarkers in breast cancer.

Implications: ERα directs DNA methylation-mediated silencing of specific genes that have biomarker potential in breast cancer subtypes. Mol Cancer Res; 15(2); 152-64. ©2016 AACR.

MeSH terms

  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • DNA Methylation*
  • Epithelial-Mesenchymal Transition / genetics*
  • Estrogen Receptor alpha / biosynthesis
  • Estrogen Receptor alpha / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Humans
  • MCF-7 Cells
  • Neoplastic Stem Cells / physiology*


  • ESR1 protein, human
  • Estrogen Receptor alpha