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

Stone, Andrew, Zotenko, Elena, Locke, Warwick J., Korbie, Darren, Millar, Ewan K. A., Pidsley, Ruth, Stirzaker, Clare, Graham, Peter, Trau, Matt, Musgrove, Elizabeth A., Nicholson, Robert I., Gee, Julia M. W. and Clark, Susan J. 2015. DNA methylation of oestrogen-regulated enhancers defines endocrine sensitivity in breast cancer. Nature Communications 6 , 7758. 10.1038/ncomms8758

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RM Therapeutics. Pharmacology
Additional Information: This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license
Publisher: Nature Research
ISSN: 2041-1723
Funders: The Cancer Institute NSW, Cancer Research UK, Breast Cancer Campaign UK;, NHMRC Fellowship, National Health and Medical Research Council, National Breast Cancer Foundation
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 6 June 2015
Last Modified: 14 Sep 2020 10:00
URI: http://orca.cf.ac.uk/id/eprint/75922

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