Investigating the Impact of ABL Kinase Signaling on Epigenetic Reprogramming in Metastatic Triple Negative Breast Cancer

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Because of its highly metastatic potential and limited treatment options, triple-negative breast cancer (TNBC) remains a leading cause of cancer associated deaths in women. Recent studies have shown that distinct chromatin landscapes correspond to metastatic relapse. Our lab has shown that the Abelson (ABL) family of non-receptor tyrosine kinases promote metastasis of breast cancer cells through activation of downstream transcriptional changes. However, how these changes exist in the greater context of global chromatin dynamics has yet to be explored. My preliminary data suggest that simultaneously targeting the epigenome and the ABL kinase- regulated transcriptome might be a promising new therapeutic strategy for treating metastatic triple negative breast cancer. The overall hypothesis of the proposal is that inhibition of ABL kinases leads to distinct changes in the chromatin landscape that sensitizes TNBC cells to treatment with drugs targeting epigenetic regulatory proteins leading to TNBC cell death. The aims of the proposal are to elucidate the epigenetic landscape associated with ABL kinase signaling to promote metastatic progression, and to understand how these dynamic changes might be exploited to elicit therapeutic benefit in metastatic TNBC models. Approaches used to address these objectives will include CRISPR/Cas9 screens, ATAC-seq, and in vitro and in vivo drug treatment experiments using cell lines and mice respectively.