Oral Presentation Lowy Cancer Symposium 2015

DNA methylation of estrogen regulated enhancers defines endocrine sensitivity in breast cancer (#6)

Andrew Stone 1 2 , Elena Zotenko 2 3 , Warwick J Locke 2 3 , Darren Korbie 4 , Ewan KA Millar 5 6 , Ruth Pidsley 2 3 , Clare Stirazker 2 3 , Robert I Nicholson 7 , Julia MW Gee 7 , Susan Clark 2 3
  1. St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, St Vincent's Hospital, Sydney, NSW, Australia
  2. Epigenetics Research Program, Cancer Division, Garvan Institute of Medical Research, Sydney, NSW, Australia
  3. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  4. Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD, Australia
  5. Translational Breast Cancer Research, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW, Australia
  6. Department of Anatomical Pathology, South Eastern Area Laboratory Service, St George Hospital, Kogarah, NSW, Australia
  7. Department of Radiation Oncology, Cancer Care Centre, St George Hospital, Kogarah, NSW, Australia

Expression of estrogen receptor (ESR1) determines whether a breast cancer patient receives endocrine therapy as part of their adjuvant care, but does not guarantee patient response1. ESR1-positive patients with either intrinsic or acquired resistance to endocrine therapy represent almost a quarter of all breast cancer cases; yet the molecular factors that define endocrine response in ESR1-positive breast cancer patients remain poorly understood1, 2. 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 estrogen-responsive enhancer, not promoter regions, 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 the transition from normal mammary epithelial cells to endocrine responsive ESR1-positive breast 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. 

  1. Musgrove, E.A. & Sutherland, R.L. Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer 9, 631-643 (2009).
  2. EBCTCG Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. The Lancet 365, 1687-1717 (2005).