A new role for ERα: Silencing via DNA methylation of basal, stem cell, and EMT genes

Ariazi, E. A., Taylor, J. C., Black, M. A., Nicolas, E., Slifker, M. J., Azzam, D. J., Boyd, J. (2017) A new role for ERα: Silencing via DNA methylation of basal, stem cell, and EMT genes. Molecular Cancer Research, 15 (2). pp. 152-164. ISSN 1541-7786

Abstract

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.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > DNA methylation
diseases & disorders > cancer > cancer types > breast cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation
CSHL Authors:
Communities: CSHL labs > Boyd lab
Highlight: Boyd, Jeff
Depositing User: Adrian Gomez
Date: 2017
Date Deposited: 13 Mar 2020 18:47
Last Modified: 28 May 2020 21:31
PMCID: PMC5308451
Related URLs:
URI: https://repository.cshl.edu/id/eprint/39209

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