Impact of Disrupted BRCA2 Protein-Protein Interactions on DNA Repair and Tumorigenesis

摘要

In this report, we have investigated the effects of overexpression of active Ras within the mammary epithelium. Using the tetracycline-inducible system, we have generated a line of mice which, when also bearing rtTA transgene expressed under control of the MMTV LTR, inducibly express active H-Ras in the mammary epithelium in response to the drug doxycycline. We have also shown that pathways downstream of Ras are activated, such as the Raf/MEK/MAPK pathway. We have shown that the mammary epithelium undergoes an increase in proliferation in response to Ras, but undergoes a proliferative arrest and inhibition of ductal elongation in chronically induced glands. This arrest occurs in the absence of increased apoptosis. Removal of doxycycline abrogates the growth arrest and restores a normal gland within 60 days. Finally, the pl9/p53/p2l pathway is activated in response to Ras.