BCL-2 hypermethylation is a potential biomarker of sensitivity to anti-mitotic chemotherapy in endocrine-resistant breast cancer.
Overexpression of the anti-apoptotic factor, BCL-2, is a frequent feature of malignant disease and is commonly associated with poor prognosis and resistance to conventional chemotherapy. In breast cancer, however, high BCL-2 expression is associated with favourable prognosis, estrogen receptor (ER) positivity and low tumour grade; whilst low expression is included in several molecular signatures associated with resistance to endocrine therapy. In the present study, we correlate BCL-2 expression and DNA methylation profiles in human breast cancer and in multiple cell models of acquired endocrine-resistance to determine whether BCL-2 hypermethylation could provide a useful biomarker of response to cytotoxic therapy. In human disease, diminished expression of BCL-2 was associated with hypermethylation of the second exon, in a region that overlapped a CpG island and an ER-binding site. Hypermethylation of this region, which occurred in 10% of primary tumours, provided a stronger predictor of patient survival (p=0.019) when compared to gene expression (n=522). In multiple cell-models of acquired endocrine-resistance, BCL-2 expression was significantly reduced in parallel with increased DNA methylation of the exon 2 region. The reduction of BCL-2 expression in endocrine-resistant cells lowered their apoptotic threshold to anti-mitotic agents: nocodazole, paclitaxel and the PLK1 inhibitor, BI2536. This phenomenon could be reversed with ectopic expression of BCL-2, and rescued with the BCL-2 inhibitor, ABT-737. Collectively, these data imply that BCL-2 hypermethylation provides a robust biomarker of response to current and next generation cytotoxic agents in endocrine-resistant breast cancer, which may prove beneficial in directing therapeutic strategy for patients with non-resectable, metastatic disease.
|Authors||Stone, A.; Cowley, M.J.; Valdes-Mora, F.; McCloy, R.; Sergio, C.M.; Gallego-Ortega, D.; Caldon, C. E.; Ormandy, C.J.; Biankin, A.V.; Gee, J. M.; Nicholson, R. I.; Print, C.G.; Clark, S.J.; and Musgrove, E.A.;|
|Responsible Garvan Author|
|Publisher Name||MOLECULAR CANCER THERAPEUTICS|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/11629|