Abstract/Project Summary Every year, breast cancer kills more than a half-million women worldwide. Monumental efforts have made an impact toward understanding primary disease and the development of targeted therapies. Yet, these therapies still fail many women initially, and others relapse with therapy-resistant disease. Thus, we must focus on developing better tools to predict disease susceptibility in those at higher risk, while augmenting the search for molecularly based strategies to prevent breast cancer. More specifically, mutations in the BRCA1 genes, and their consequent loss of function, are the most clinically relevant genomic alterations that increase the susceptibility of individuals to breast cancer. Still, not all women with BRCA1 mutations will develop breast cancer. Thus, we need a clear picture of the mechanisms that govern cancer susceptibility. Our main goal is to define how the epigenome alters the development of Brca-1 deficient mammary tumors. We previously demonstrated that the mammary epithelium epigenome and specific chromatin remodeling factors play a role in oncogenesis progression. Now, we hypothesize that the epigenome similarly contributes to the development of BRCA1 mutant breast tumors. We will use innovative models of mammary oncogenesis to specifically dissect epigenetic mechanisms that influence the development of Brca1-deficient mammary tumors. By investigating the effects of a specific epigenetic regulator (BPTF) and a global epigenomic program (pregnancy) on mammary tumor progression, we may also identify prognostic biomarkers that will enable us to identify women who will benefit from therapy. Ultimately, we hope to validate our hypotheses pre-clinically using normal and malignant human breast organoid cultures, to aid the development of strategies that will be useful as primary prevention in humans.