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.
Original language | English |
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Pages (from-to) | 152-164 |
Number of pages | 13 |
Journal | Molecular Cancer Research |
Volume | 15 |
Issue number | 2 |
DOIs | |
State | Published - Feb 1 2017 |
Keywords
- Breast Neoplasms/genetics
- DNA Methylation
- Epithelial-Mesenchymal Transition/genetics
- Estrogen Receptor alpha/biosynthesis
- Female
- Gene Expression Regulation, Neoplastic
- Gene Silencing
- Humans
- MCF-7 Cells
- Neoplastic Stem Cells/physiology