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

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

SUBMITTER: Ariazi EA 

PROVIDER: S-EPMC5308451 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature