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

Resistance to hormonal therapies is a major clinical problem in the treatment of estrogen receptor alpha-positive (ER alpha(+)) breast cancers. Epigenetic marks, namely DNA methylation of cytosine at specific CpG sites (5mCpG), are frequently associated with ER alpha(+) status in human breast cancers. Therefore, ER alpha 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 ER alpha(+) cells but derepressed upon exposure to the demethylating agent decitabine, derepressed upon long-term loss of ER alpha expression, and resuppressed by gain of ER alpha activity/expression. ER alpha-dependent DNA methylation targets (n = 39) were enriched for ER alpha-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 ER alpha expression/activity and contain ER alpha-binding sites. Thus, genes that are methylated in an ER alpha-dependent manner may serve as predictive biomarkers in breast cancer. (C) 2016 AACR.