DNA methylation of oestrogen-regulated enhancers defines endocrine sensitivity in breast cancer.

Abstract

Expression of oestrogen receptor (ESR1) determines whether a breast cancer patient receives endocrine therapy, but does not guarantee patient response. The molecular factors that define endocrine response in ESR1-positive breast cancer patients remain poorly understood. Here we characterize the DNA methylome of endocrine sensitivity and demonstrate the potential impact of differential DNA methylation on endocrine response in breast cancer. We show that DNA hypermethylation occurs predominantly at oestrogen-responsive enhancers and is associated with reduced ESR1 binding and decreased gene expression of key regulators of ESR1 activity, thus providing a novel mechanism by which endocrine response is abated in ESR1-positive breast cancers. Conversely, we delineate that ESR1-responsive enhancer hypomethylation is critical in transition from normal mammary epithelial cells to endocrine-responsive ESR1-positive cancer. Cumulatively, these novel insights highlight the potential of ESR1-responsive enhancer methylation to both predict ESR1-positive disease and stratify ESR1-positive breast cancer patients as responders to endocrine therapy.

• Authors: Andrew Stone, Elena Zotenko, Warwick J Locke, Darren Korbie, Ewan K A Millar, Ruth Pidsley, Clare Stirzaker, Peter Graham, Matt Trau, Elizabeth A Musgrove, Robert I Nicholson, Julia M W Gee, Susan J Clark
• Journal: Nature communications (Nat Commun) Vol. 6 Pg. 7758 (Jul 14 2015) ISSN: 2041-1723 [Electronic] England
• PMID: 26169690 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Hormonal
• ESR1 protein, human
• Estrogen Receptor alpha
• Tamoxifen

Topics

• Adult
• Aged
• Antineoplastic Agents, Hormonal (therapeutic use)
• Breast Neoplasms (drug therapy, genetics, metabolism)
• Carcinoma, Ductal, Breast (drug therapy, genetics, metabolism)
• Carcinoma, Lobular (drug therapy, genetics, metabolism)
• Chromatin Immunoprecipitation
• DNA Methylation (genetics)
• Drug Resistance, Neoplasm (genetics)
• Enhancer Elements, Genetic (genetics)
• Estrogen Receptor alpha (genetics, metabolism)
• Female
• Humans
• MCF-7 Cells
• Middle Aged
• Multiplex Polymerase Chain Reaction
• Tamoxifen (therapeutic use)