Poster Presentation 25th Lorne Cancer Conference 2013

BCL-2 expression is silenced by DNA hypermethylation in human breast cancer, providing a potential biomarker of sensitivity to mitotic inhibition. (#364)

Andrew Stone 1 , Mark J Cowley 1 , Fatima Valdes Mora 1 , Rachael A McCloy 1 , C.Marcelo Sergio 1 , David Gallego Ortega 1 , C.Elizabeth Caldon 1 , Christopher J Ormandy 1 2 , Andrew V Biankin 1 2 , Julia MW Gee 3 , Robert I Nicholson 3 , Cristin G Print 4 , Susan J Clark 1 2 , Robert L Sutherland 1 2 , Elizabeth A Musgrove 1 2
  1. The Kinghorn Cancer Centre & Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. St Vincent's Clinical School, Faculty of Medicine, UNSW, St Vincent's Hospital, Sydney, NSW, Australia
  3. Breast Cancer Molecular Pharmacology Group, Cardiff University, Cardiff, Wales, UK
  4. Bioinformatics of Disease, School of Medical Sciences, University of Auckland, Auckland, New Zealand

At the time of diagnosis, approximately 70% of breast cancer patients are classified as estrogen-receptor (ER) positive and consequently receive some form of endocrine therapy, most commonly the selective ER modulator, tamoxifen. Whilst endocrine therapies almost halve the rate of disease recurrence, their efficacy is limited by intrinsic and acquired resistance [1]. Therapeutic options for patients with endocrine-resistant disease remain limited and disease progression is almost inevitable, highlighting the need for both better predictive biomarkers of response and new therapeutic strategies. To this end, low expression of BCL-2, an anti-apoptotic factor that is regulated by the ER in breast cancer cells, has been included in several molecular signatures associated with tamoxifen failure and poor prognosis in primary breast cancer [2]. Whilst the mechanism of gene suppression remains unknown, this raises the possibility that patients with endocrine-resistant disease may achieve significant therapeutic benefit from anti-mitotic chemotherapies, since low BCL-2 expression is associated with increased apoptotic response [3].

In the present study, we demonstrate that BCL2 expression was suppressed by promoter hypermethylation in approximately 10% (55/522) of all patients in the Cancer Genome Atlas breast cohort [4], and that DNA methylation provided a stronger predictor of disease specific survival (DSS) compared gene expression. The specific region of DNA whose methylated status correlated with gene expression and DSS contained an ER-binding site and was heavily methylated in tamoxifen resistant vs sensitive breast cancer cells in vitro. The absence of BCL2 in tamoxifen-resistant cells served to lower their apoptotic threshold to paclitaxel and PLK1 inhibitor, BI2536, compared to tamoxifen-sensitive cells; a phenomenon that could be reversed with ectopic expression of BCL2, and rescued with BCL2 inhibitor, ABT737.

These data infer that BCL-2 hypermethylation could provide a robust biomarker of response to current and next generation inhibitors of mitosis in endocrine-resistant breast cancer.

  1. Musgrove EA, Sutherland RL. Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer. 2009;9(9):631-43.
  2. Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, et al. A Multigene Assay to Predict Recurrence of Tamoxifen-Treated, Node-Negative Breast Cancer. New England Journal of Medicine. 2004;351(27):2817-26.
  3. Huang H-C, Shi J, Orth JD, Mitchison TJ. Evidence that Mitotic Exit Is a Better Cancer Therapeutic Target Than Spindle Assembly. Cancer Cell. 2009;16(4):347-58.
  4. TCGA. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61-70.