The Role of BRCA1 in Suppressing Epithelial-Mesenchymal Transition in Mammary Gland and Tumor Development

Abstract

Abstract : During the funding period, the PI has found that disrupting Brca1 by either germline or epithelium-specific mutation in p18-deficient mice activates epithelial-to-mesenchymal transition (EMT) and induces dedifferentiation of luminal stem cells (LSCs), which associate closely with expansion of basal and cancer stem cells and formation of basal-like tumors. Mechanistically,BRCA1 bound to the TWIST promoter, suppressing its activity and inhibiting EMT in mammary tumor cells.PI has also found that p16 loss transforms Brca1-deficient mammary epithelial cells and induces mammary tumors, thoughp16 loss alone is not sufficient to induce mammary tumorigenesis. PI has demonstrated that loss of both p16 and Brca1 leads to metastatic, basal-like, mammary tumors with the induction of EMT and an enrichment of tumor initiating cells. Together, our findings show that BRCA1 suppresses TWIST and EMT, inhibits LSC dedifferentiation and represses expansion of basal stem cells and basal-like tumors. In addition, we provide the first genetic evidence directly showing that p16 which is frequently deleted and inactivated in human breast cancers, collaborates with Brca1 controlling mammary tumorigenesis.