Dysregulation of the epigenome in human breast cancer: contributions of gene-specific DNA hypermethylation to breast cancer pathobiology and targeting the breast cancer methylome for improved therapy.

Triple-negative breast cancers (including basal-like and claudin-low molecular subtypes) represent 20% to 25% of all breast cancers, but disproportionately contribute to breast cancer-associated death. We have identified a novel fundamental biological property of triple-negative breast cancers: most triple-negative breast cancers express aberrant DNA hypermethylation due to overexpression of DNA methyltransferase 3b (and hyperactivity of the DNA methyltransferase enzymes). DNA methyltransferase 3b overexpression occurs secondary to loss of miRNA-mediated post-transcriptional regulation. The resulting hyperactivity of DNA methyltransferase 3b produces concurrent DNA methylation-dependent silencing of numerous critical gene targets (including tumor suppressors and pro-apoptotic genes) and resistance to cytotoxic chemotherapy. This observation presents new opportunities for development of innovative treatment strategies on the basis of the epigenome as a novel therapeutic target in triple-negative breast cancers. Epigenetic therapy represents a new principle in cancer treatment in which restoration of critical molecular pathways occurs secondary to reexpression of silenced genes that encode negative mediators of cancer cell growth.