Project Summary/Abstract Aggressive receptor triple-negative breast cancers (TNBCs) lack effective biomarkers or targeted treatments, posing a major clinical challenge. Examination of primary clinical data from the multi-institutional ISPY trial found that elevated MYC oncogene expression is a strong indicator of lethal TNBC. A growing body of work suggests that non-coding RNAs may play an essential role in MYC dependent pathologies, however which of these may be essential for survival and progress of MYC-driven tumors remains unknown. This proposal will address the discovery of mechanisms that determine the initiation, risk, and susceptibility for the most deadly type of breast cancer, basal-like or triple negative breast cancer (TNBC) and the identification of new mediators of lethality that could lead to tumor regression when blocked. We will test the hypothesis that MYC-dependent microRNAs in vivo and circular RNAs are required for breast tumor formation, maintenance and recurrence. In an unbiased in vitro screen of ~1000 individual locked nucleic acid (LNA) microRNA antagonists (antimiRs) we identified 13 miRNAs that are required for MYC-dependent cancer progression in human mammary epithelial cells (HMEC) and are highly expressed in “high Myc” breast cancers from the TCGA dataset. We found that putative oncogenic circPVT1 had significantly up-regulated expression in MYC-high TNBC cell line HCC1143 relative to MYC-low T47D breast cancer cells. Thus, we will sequence and functionally validate Myc dependent miRNAs and circRNAs in these studies. The long-term goal is to identify critical non-coding RNA targets whose inhibition can block TNBC tumor growth. Aim 1: Target MYC-driven miRNA vulnerabilities in vivo: We will test the in vivo efficacy of antimiRs conjugated to folate via RNA nanoparticles targeting miR-16, miR-23, miR-107 and miR-144 using a conditional MYC-driven transgenic model of breast cancer. Aim 2: Show circRNAs are required for MYC driven breast cancer: We plan to determine the functional consequences of perturbing Myc-dependent circRNAs in human and mouse breast cancer using lenti-shRNA and circRNA overexpression in a high throughput screen. My goal is to become a principal investigator pursuing an independent research program focused on deciphering the disease mechanisms of breast cancer. UCSF is an ideal environment to pursue an interdisciplinary approach to breast cancer research. Completion of the work proposed will allow me to develop skills and a collaborative network necessary to compete for tenure track principal investigator positions. This proposal will address the discovery of non-coding RNA mechanisms that determine the initiation, risk, and susceptibility for the most deadly type of breast cancer, basal-like or triple negative breast cancer (TNBC) and the identification of new drivers that could lead to tumor regression when blocked.