BCL-2 Hypermethylation Is a Potential Biomarker of Sensitivity to Antimitotic Chemotherapy in Endocrine-Resistant Breast Cancer

Abstract

Overexpression of the antiapoptotic 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 favorable prognosis, estrogen receptor (ER) positivity, and low tumor grade, whereas 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 tumors, provided a stronger predictor of patient survival (P ¼ 0.019) when compared with gene expression (n ¼ 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 antimitotic 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 nonresectable, metastatic disease. Mol Cancer Ther; 12(9); 1874-85. Ó2013 AACR.

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax

“…A clinical study is now underway in Australia to explore the venetoclax-tamoxifen combination in patients with metastatic ER-positive HER2-non-amplified breast cancer (see Table 1). Treatment with ABT-737 has also been shown to restore sensitivity to paclitaxel in endocrine-resistant breast cancer (129). Additional approaches combining BH3 mimetics with investigational agents such as PI3K/mTOR inhibitors (130, 131) and gamma secretase inhibitors (132) are also being explored to bypass resistance mechanisms and enhance efficacy.…”

FOXM1 participates in PLK1-regulated cell cycle progression in renal cell cancer cells

“…The serine/threonine kinase PLK1 governs several mitotic stages, including entry into mitosis, centrosome maturation, bipolar spindle assembly, activation of the anaphase-promoting complex/cyclosome by phosphorylation of early mitotic inhibitor 1, chromosome segregation and mitotic exit (4). The overexpression of PLK1 is associated with a poor prognosis in a variety of cancers (5)(6)(7)(8)(9). Beyond the regulation of mitosis, PLK1 possesses cancer cell-specific functions in G1/S transition and DNA replication (10,11).…”

Methylome sequencing in triple-negative breast cancer reveals distinct methylation clusters with prognostic value

“…A number of studies have documented aberrant methylation events in breast carcinogenesis and identified specific DNA methylation biomarkers that have significant diagnostic and prognostic potential [9][10][11][12] . Several studies have also identified DNA methylation signatures that can distinguish between breast cancer subtypes [13][14][15][16] , and others that may be predictive of treatment response [17][18][19] .…”