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A New Role for ERalpha: Silencing via DNA Methylation of Basal, Stem Cell, and EMT Genes
Mol Cancer Res. 2017 Feb;15(2) :152-164
PMID: 28108626 PMCID: PMC5308451 URL: https://www.ncbi.nlm.nih.gov/pubmed/28108626
AbstractResistance to hormonal therapies is a major clinical problem in the treatment of estrogen receptor alpha-positive (ERalpha+) breast cancers. Epigenetic marks, namely DNA methylation of cytosine at specific CpG sites (5mCpG), are frequently associated with ERalpha+ status in human breast cancers. Therefore, ERalpha 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 ERalpha+ cells but derepressed upon exposure to the demethylating agent decitabine, derepressed upon long-term loss of ERalpha expression, and resuppressed by gain of ERalpha activity/expression. ERalpha-dependent DNA methylation targets (n = 39) were enriched for ERalpha-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 ERalpha expression/activity and contain ERalpha-binding sites. Thus, genes that are methylated in an ERalpha-dependent manner may serve as predictive biomarkers in breast cancer. IMPLICATIONS: ERalpha directs DNA methylation-mediated silencing of specific genes that have biomarker potential in breast cancer subtypes. Mol Cancer Res; 15(2); 152-64. (c)2016 AACR.
NotesAriazi, Eric A Taylor, John C Black, Michael A Nicolas, Emmanuelle Slifker, Michael J Azzam, Diana J Boyd, Jeff eng P30 CA006927/CA/NCI NIH HHS/ 2017/01/22 06:00 Mol Cancer Res. 2017 Feb;15(2):152-164. doi: 10.1158/1541-7786.MCR-16-0283. Epub 2016 Nov 15.