title: 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.affiliation: 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.
authors.forename: Andrew
authors.initials: A
authors.lastname: Stone
authors.affiliation: 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.
authors.forename: Elena
authors.initials: E
authors.lastname: Zotenko
authors.affiliation: 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.
authors.forename: Warwick J
authors.initials: WJ
authors.lastname: Locke
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Darren
authors.initials: D
authors.lastname: Korbie
authors.affiliation: 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.
authors.forename: Ewan K A
authors.initials: EK
authors.lastname: Millar
authors.affiliation: 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.
authors.forename: Ruth
authors.initials: R
authors.lastname: Pidsley
authors.affiliation: 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.
authors.forename: Clare
authors.initials: C
authors.lastname: Stirzaker
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Graham
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Matt
authors.initials: M
authors.lastname: Trau
authors.affiliation: 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.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Musgrove
authors.affiliation: Breast Cancer Molecular Pharmacology Group, School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Wales CF10 3NB, UK.
authors.forename: Robert I
authors.initials: RI
authors.lastname: Nicholson
authors.affiliation: Breast Cancer Molecular Pharmacology Group, School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Wales CF10 3NB, UK.
authors.forename: Julia M W
authors.initials: JM
authors.lastname: Gee
authors.affiliation: 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.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Clark
mesh_terms: D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D018275:Carcinoma, Lobular / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction; D013629:Tamoxifen / Q000627:therapeutic use
chemical_list: D018931:Antineoplastic Agents, Hormonal; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D013629:Tamoxifen