+44 330 818 7254Pavan Kumar Puvvula
Breast cancer is a constellation of diseases, with different molecular etiologies and signatures that determine cell behaviors and risk of metastasis and death. Despite significant progress in defining molecular signatures of different types of breast cancer, there are major gaps in understanding the mechanisms that regulate them. Nearly half of all cancer driver mutations are in genes encoding chromatin modifiers. The resulting epigenetic changes promote cancer cell hallmarks: Hence the ability to disrupt the function of epigenome regulators might hold a key to develop effective epigenetic therapies. We previously showed that CAPER? (Coactivator of AP1 and Estrogen Receptor) prevents senescence of primary cells by regulating epigenetic marks. Since CAPER???? is overexpressed in many cancers and interacts with other oncoproteins, we investigated its functions and partners in breast cancer. We discovered a novel complex between CAPER? and the histone methyltransferase MLL1 (CAP/MLL1). The CAP/MLL1 complex is present in human luminal and basal breast cancers and BC cell lines, but not present in normal breast cells, primary mammary epithelial cells, nor is it detected in any of the other normal human tissues we have tested (brain, lung, liver, bone marrow, intestine). CAP/ MLL1 occupies and regulates thousands of targets genes and functions high in the hierarchy controlling transcription by regulating chromatin marks and expression of critical cell cycle genes in both luminal (ER+) and basal-like (ER-) BCs. Remarkably, we found that CAP/MLL1 occupies and regulates ~ 30 % of the 137 cancer “driver genes”3 in BCCs. Further, we have determined that the RRM3 domain of CAPER? is critical for CAP/MLL1 complex formation and can function as a dominant-negative to disrupt MLL1 occupancy and H3K4 trimethylation of target genes, decrease expression of pro-proliferation and cancer progression genes, all of which result in decreased BC cell growth. An RRM3-derived cell penetrating peptide restricted the growth of BC cells but does not perturb the growth of primary cells, demonstrating cancer-specific therapeutic potential for CAP/MLL1 complex disruption in BC.
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