Detecting and Targeting Oncogenic Myc in Breast Cancer

Our idea is that in addition to the target genes regulated by Myc in nontransformed cells, constitutively activated and overexpressed Myc protein in tumor cells will directly bind and regulate a unique set of target genes that directly contribute to the carcinogenic process. For example, at high levels of expression, Myc may bind low affinity sites and regulate a distinct cohort of targets by a unique mechanism of action. By identifying this transformation specific subset of Myc target genes we aim to develop a diagnostic tool to identify oncogenic Myc activity in breast tumor cells. We also aim to develop a unique anti-cancer therapeutic that will potentially target this unique transforming activity of Myc. The TRRAP cofactor has been shown to be essential for Myc to drive transformation. This suggests blocking MycTRRAP interaction will inhibit the carcinogenic program directed by oncogenic Myc. By conducting the experiments outlined in this proposal we will test a unique hypothesis and will make significant contributions to the molecular diagnosis and treatment of breast cancer that can be applied to the clinic in a timely manner. Specific Aims 1 Identify tumor-specific, directly-regulated Myc target genes in transformed HMECs and develop a definitive diagnostic tool to detect oncogenic Myc activity in breast cancer. 2 Isolate small molecular weight inhibitors that can disrupt MycTRRAP interaction in vivo and identify MycTRRAP co-bound target genes in breast cancer.