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

Author

Listed:
  • Andrew Stone

    (Epigenetics Research Program, Garvan Institute of Medical Research
    Faculty of Medicine, St Vincent’s Clinical School, UNSW, NSW 2052 & St Vincent’s Hospital)

  • Elena Zotenko

    (Epigenetics Research Program, Garvan Institute of Medical Research
    Faculty of Medicine, St Vincent’s Clinical School, UNSW, NSW 2052 & St Vincent’s Hospital)

  • Warwick J. Locke

    (Epigenetics Research Program, Garvan Institute of Medical Research
    Faculty of Medicine, St Vincent’s Clinical School, UNSW, NSW 2052 & St Vincent’s Hospital)

  • Darren Korbie

    (Australian Institute for Bioengineering and Nanotechnology, University of Queensland)

  • Ewan K. A. Millar

    (Translational Breast Cancer Research, The Kinghorn Cancer Centre, Garvan Institute of Medical Research
    South Eastern Area Laboratory Service, St George Hospital, Kogarah
    School of Medicine and Health Sciences, University of Western Sydney, Campbelltown
    Faculty of Medicine, UNSW)

  • Ruth Pidsley

    (Epigenetics Research Program, Garvan Institute of Medical Research
    Faculty of Medicine, St Vincent’s Clinical School, UNSW, NSW 2052 & St Vincent’s Hospital)

  • Clare Stirzaker

    (Epigenetics Research Program, Garvan Institute of Medical Research
    Faculty of Medicine, St Vincent’s Clinical School, UNSW, NSW 2052 & St Vincent’s Hospital)

  • Peter Graham

    (Faculty of Medicine, UNSW
    Cancer Care Centre, St George Hospital, Kogarah)

  • Matt Trau

    (Australian Institute for Bioengineering and Nanotechnology, University of Queensland)

  • Elizabeth A. Musgrove

    (Faculty of Medicine, St Vincent’s Clinical School, UNSW, NSW 2052 & St Vincent’s Hospital
    Translational Breast Cancer Research, The Kinghorn Cancer Centre, Garvan Institute of Medical Research
    Wolfson Wohl Cancer Research Centre, University of Glasgow)

  • Robert I. Nicholson

    (Breast Cancer Molecular Pharmacology Group, School of Pharmacy and Pharmaceutical Sciences, Cardiff University)

  • Julia M. W. Gee

    (Breast Cancer Molecular Pharmacology Group, School of Pharmacy and Pharmaceutical Sciences, Cardiff University)

  • Susan J. Clark

    (Epigenetics Research Program, Garvan Institute of Medical Research
    Faculty of Medicine, St Vincent’s Clinical School, UNSW, NSW 2052 & St Vincent’s Hospital)

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.

Suggested Citation

  • 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., 2015. "DNA methylation of oestrogen-regulated enhancers defines endocrine sensitivity in breast cancer," Nature Communications, Nature, vol. 6(1), pages 1-9, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8758
    DOI: 10.1038/ncomms8758
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    Cited by:

    1. Mahnaz Hosseinpour & Xinqi Xi & Ling Liu & Luis Malaver-Ortega & Laura Perlaza-Jimenez & Jihoon E. Joo & Harrison M. York & Jonathan Beesley & C. Elizabeth Caldon & Pierre-Antoine Dugué & James G. Dow, 2024. "SAM-DNMT3A, a strategy for induction of genome-wide DNA methylation, identifies DNA methylation as a vulnerability in ER-positive breast cancers," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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