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 = 0.019) when compared with 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 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.
Highlights
At least 70% of breast cancers are classified as estrogen receptor (ER)–positive, and the majority of patients with this disease receive some form of endocrine therapy as part of their adjuvant care [1]
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
BCL-2 methylation in human breast cancer To determine whether BCL-2 expression in human breast cancer correlated with DNA methylation, we examined Illumina 450k Methylation Array and RNASeq data from TCGA breast cohort [25]
Summary
At least 70% of breast cancers are classified as estrogen receptor (ER)–positive, and the majority of patients with this disease receive some form of endocrine therapy as part of their adjuvant care [1]. Endocrine therapy reduces the risk of disease recurrence, 28% of patients with luminal A and 43% with luminal B breast. Metastases will most commonly form in the bone (19% of luminal A, 30% of luminal B), and in the brain, lung, and liver, ruling out surgical intervention for most patients [2]. The median duration of survival from time of relapse is 2.2 and 1.6 years for patients with luminal A and luminal B breast cancer, respectively [2], highlighting the need for more effective therapeutic approaches to metastatic disease, with companion biomarkers of response that can be profiled in the absence of a tumor biopsy
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