Pathways that Can Repair Brca1 Cancer Gene Mutation Clarified in Mice
In a new study in mice, scientists have compensated for mutations in the Brca1 gene that can lead to cancer by deleting a second gene, which then lessens the probability of cancer. Mouse Brca1-associated mammary tumors have significant similarities to human BRCA1- associated (BReast CAncer 1, early onset) breast cancer in regard to tumor aggressiveness, high incidence, mutations and genetic instability. The study, led by scientists at National Cancer Institute (NCI), part of the National Institutes of Health, and their colleagues, appeared online April 1, 2010 and in print April 16, 2010, in the journal Cell.
In humans, mutations in the BRCA1 gene increase the risk of breast, ovarian, and other cancers by impairing an important pathway for the repair of damaged DNA. Lead investigator Andre Nussenzweig, Ph.D., head of the Molecular Recombination Section of NCIs Experimental Immunology Branch, and his colleagues found that when a gene known as 53BP1 was also defective, the formation of the mammary tumors that normally develop in Brca1 mutant mice was suppressed. Moreover, they found that inactivation of 53BP1 restored the DNA repair function that is lost when Brca1is mutated.
The protein produced by the Brca1 gene participates in an important DNA repair pathway called homologous recombination (HR). This pathway is used to repair a type of DNA damage called replication-associated chromosome breaks, which develop spontaneously when cells divide. When HR is defective, whether through Brca1 mutations or mutations in other genes whose products are involved in this pathway, cells must rely on alternative DNA repair pathways. These other pathways are more error-prone, or mutagenic, than HR, and they can lead to the formation of abnormal and unstable chromosome structures. The resulting genomic instability increases the risk of tumor development.
Women who carry a harmful mutation in the BRCA1 gene have up to an 85 percent lifetime risk of developing breast cancer, and up to a 40 percent lifetime risk of developing ovarian cancer. To date, there are no effective or targeted therapies that overcome the breast cancer susceptibility caused by mutations in BRCA1. Promoting HR by using drugs that inhibit toxic pathways for DNA repair could greatly reduce the development of breast and ovarian cancer in women with BRCA1 mutations, said Nussenzweig.
The team used a strain of mice, originally developed by NIH researchers, that have a defective Brca1 gene. These mice frequently develop mammary tumors, which are similar to human breast cancers. Nussenzweig and colleagues found when the mice also were lacking the function of a protein called 53BP1, mammary tumor formation was largely suppressed.