Investigating the Role of BRCA1 in the Regulation of Osteoprotegerin

Recent evidence has implicated receptor activator of nuclear factor-κB (RANK)-associated signaling in the pathogenesis of BRCA1-associated breast cancer. BRCA1 mutation carriers at high risk of developing breast cancer have lower circulating levels osteoprotegerin (OPG), the endogenous inhibitor of RANK signaling, compared to non-carriers. A preliminary study by our group found a significant inverse association between circulating blood OPG levels and BRCA-associated breast cancer risk. My thesis project aimed to investigate the molecular mechanisms underlying the systemic reductions in OPG levels in BRCA1 mutation carriers using cell models of BRCA1 knockdown. My data showed that in U2OS, a bone-derived cell line, BRCA1 knockdown did not alter OPG protein nor mRNA expression. Conversely, in an immortalized human mammary epithelial cell line, suppression of BRCA1 expression decreased OPG secretion and OPG transcript levels. In sum, my findings suggest that BRCA1 may have a mammary-specific role in modulating OPG secretion through a transcriptional mechanism.M.Sc