Epigenetic Subtypes of Triple-Negative Breast Cancer

Abstract : Triple negative breast cancer (TNBC) is the only major breast tumor subtype that lacks targeted therapy and mainly due to this has poor outcome. The majority of TNBCs have basal/stem cell-like phenotypes implying inability to respond to luminal differentiation-inducing stimuli. Using somatic cell genetics we determined that the basal phenotype is generally dominant. Based on the analysis of a limited number of TNBC cell lines we found that the epigenetic profiles of TNBCs are highly heterogeneous and subtypes defined based on chromatin modification patterns do not overlap with classification based on gene expression profiles. To further dissect the epigenetic heterogeneity of TNBCs, we have characterized the histone H3 lysine 27 acetylation (H3K27ac) profiles of a large panel (50) TNBC cell lines and primary cultures derived from patient samples. We also included luminal cells as controls. We detected distinct clustering patterns with major luminal-basal branches. However, a subset of TNBCs, enriched for those derived from pleural effusion and distant metastases, clustered closer to luminal lines rather than to other TNBCs. This observation raises the possibility that distant metastases of TNBCs are epigenetically more luminal, which has implications for systemic therapies designed to eliminate these lesions. We have also characterized the global DNA methylation profiles of a panel of TNBC lines before and after the down regulation or pharmacologic inhibition of the KDM4C histone demethylase. Interestingly, modulating KDM4Cs activity appears to lead to changes in DNA methylation patterns linking regulators of histone and DNA methylation.