(236g) Epigenetic Engineering to Target an Anti-Cancer Gene Module in Breast Cancer (Invited Speaker)

Mounting evidence from genome-wide comparisons of chromosome packaging and gene expression suggests that hyper-repression of groups of genes distinguishes cancerous cells from healthy cells. Certain members of the chromatin system (genomic DNA, RNA, and nuclear proteins) have been implicated as drivers of metastasis and cancer drug resistance. Since the early 1990’s small compounds have been used to disrupt hyper-repressed chromatin to simultaneously activate sets of therapeutic genes in cancer cells. However, it is difficult to customize the biological activity of these small compound inhibitors, and they do not directly mediate RNA PolII activity. To address these limitations, our lab has designed transcription-regulating fusion proteins that bind epigenetic marks within chromatin. We have developed the “Polycomb-based transcription factor” (PcTF), a fusion protein that reads histone modifications through a protein-protein interaction between its N-terminal Polycomb chromodomain (PCD) motif and trimethylated lysine 27 of histone H3 (H3K27me3). The C-terminal VP64 domain of PcTF recruits endogenous activators to silenced targets. We identified a set of 104 genes that become consistently activated from 24 - 72 hours after PcTF-overexpression in a triple negative breast cancer cell line (BT-549). PcTF-positive BT-549 cells show poor survival in vitro. We propose that the set of 104 genes, which includes tumor suppressor, type I interferon response, and epithelial cell fate genes, represents a ‘druggable’ anti-cancer gene module. These genes are rarely mutated in basal tumors and therefore may produce a therapeutic effect when they become activated. This talk will review our published results for BT-549, new data from additional PcTF-treated TNBC lines, and transcriptional profiling that suggests PcTF activates a more specific range of genes compared to small compound drugs.