Role of Murine BRCA1 Protein Interactions in DNA Repair.

摘要

Amplification of the c-MYC oncogene has been found in five to twenty percent of breast tumors However, the molecular mechanisms by which c-MYC contributes to tumorigenesis is not well understood. To address this question, we have used the tetracycline regulatory system to conditionally express the c- MYC oncogene in the mammary epithelium of bitransgenic mice. To determine whether c-MYC induced mammary tumors remain dependent on c-MYC for maintainenance of the tumorigenic state, we deinduced c-MYC expression in animals harboring tumors. Withdrawal of c-MYC expression revealed that nearly half of the tumors remain dependent on c-MYC transgene expression for their continued growth. To study the molecular properties that distinguish c-MYC dependent and independent tumors, c-MYC initiated tumors were analyzed for mutations in the ras family of genes. Approximately half of the tumors examined were found to harbor spontaneous activating point mutations in either K-ras or N-ras, whereas no mutations were found in H-ras. Interestingly, the presence of an activating ras mutation was found to strongly correlate with the failure of tumors to regress following c-MYC deinduction. These data suggest that spontaneous activating mutations in K-ras and N-ras represent a preferred secondary pathway for c-MYC- induced tumorigenesis in the mammary gland.