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 7758.1-7758.9. doi:10.1038/ncomms8758

Author 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.
Clark, Susan J.
Title DNA methylation of oestrogen-regulated enhancers defines endocrine sensitivity in breast cancer
Journal name Nature Communications   Check publisher's open access policy
ISSN 2041-1723
Publication date 2015-07-14
Sub-type Article (original research)
DOI 10.1038/ncomms8758
Open Access Status DOI
Volume 6
Start page 7758.1
End page 7758.9
Total pages 9
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Subject 1600 Chemistry
1300 Biochemistry, Genetics and Molecular Biology
3100 Physics and Astronomy
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.
Keyword Oestrogen receptor (ESR1)
Breast cancer
Endocrine sensitivity
Endocrine therapy
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

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