The Role of BRCA1 in Suppressing Epithelial-Mesenchymal Transition in Mammary Gland and Tumor Development
Annual rept. 1 Sep 2014-31 Aug 2015
MIAMI UNIV FL MILLER SCHOOL OF MEDICINE
Pagination or Media Count:
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. In human luminal cancer cells, BRCA1 silencing was sufficient to activate TWIST and EMT and increase tumor formation. In parallel, TWIST expression and EMT features correlated inversely with BRCA1 expression in human breast cancers. Together, our findings showed that BRCA1 suppressed TWIST and EMT, inhibited LSC dedifferentiation and repressed expansion of basal stem cells and basal-like tumors. Thus, our work offers the first genetic evidence that Brca1 directly suppresses EMT and LSC dedifferentiation during breast tumorigenesis.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research