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Nat Commun. 2015 Jul 14;6:7758. doi: 10.1038/ncomms8758.

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

Author information

1
1] Epigenetics Research Program, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia [2] Faculty of Medicine, St Vincent's Clinical School, UNSW, NSW 2052 &St Vincent's Hospital, Sydney, New South Wales 2010, Australia.
2
Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland 4072, Australia.
3
1] Translational Breast Cancer Research, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia [2] Department of Anatomical Pathology, South Eastern Area Laboratory Service, St George Hospital, Kogarah, Sydney, New South Wales 2217, Australia [3] School of Medicine and Health Sciences, University of Western Sydney, Campbelltown, Sydney, New South Wales 2560, Australia [4] Faculty of Medicine, UNSW, Kensington, New South Wales 2052, Australia.
4
1] Faculty of Medicine, UNSW, Kensington, New South Wales 2052, Australia [2] Department of Radiation Oncology, Cancer Care Centre, St George Hospital, Kogarah, Sydney, New South Wales 2217, Australia.
5
1] Faculty of Medicine, St Vincent's Clinical School, UNSW, NSW 2052 &St Vincent's Hospital, Sydney, New South Wales 2010, Australia [2] Translational Breast Cancer Research, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia [3] Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow G61 1BD, UK.
6
Breast Cancer Molecular Pharmacology Group, School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Wales CF10 3NB, UK.

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.

PMID:
26169690
PMCID:
PMC4510968
DOI:
10.1038/ncomms8758
[Indexed for MEDLINE]
Free PMC Article

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