Abstract SY28-02: Connections in the BRCA1-BRCA2 pathway of homologous recombination: Implications for breast cancer development and treatment

Abstract The breast cancer susceptibility gene, BRCA2, mediates homologous recombination (HR) via its direct interaction with the Rad51 recombinase. There is ample genetic and biological evidence that BRCA1 and BRCA2 are functioning in the same pathway of DNA repair, but the functional connection between the two proteins is poorly understood. Interestingly, a mutation of BRCA1 (S988A) localized normally to ionizing radiation induced nuclear foci (IRIF), but the BRCA2 protein could not be recruited to BRCA1 at the damage site. Phosphorylation of BRCA1 at the S988 site is carried out by Chk2, which was also required for BRCA2 to localize to sites of DNA damage and support homologous recombination. These observations suggest that CHK2-BRCA1-BRCA2-Rad51 function in a single pathway of homologous recombinational repair to prevent the development of breast cancer. In familial breast cancer, one allele of BRCA1 or BRCA2 is germline mutant and the second allele is inactivated to allow tumor development. Thus, loss of function of BRCA1/BRCA2 is a tumor-specific finding, making the role of alternative repair pathways in these cells critical for their survival. We show that loss of Rad52 function is synthetic lethal with BRCA2 deficiency, whereas there is no impact on cell growth in BRCA2-complemented cells. The frequency of both spontaneous and double-strand break-induced homologous recombination, and ionizing radiation induced Rad51 foci, decreased by greater than 50%, when Rad52 was depleted in BRCA2-deficient cells, with no effect in BRCA2-complemented cells. Ionizing radiation-induced and S-phase associated Rad52-Rad51 foci form equally well in the presence or absence of BRCA2, indicating that Rad52 can respond to DNA double strand breaks and replication stalling independently of BRCA2. The observation that Rad52-inactivation is synthetic lethal with BRCA2 and that Rad52 acts independently of BRCA2 makes Rad52 a target for therapy in these tumors. Finally, we have evidence that the BRCA1-BRCA2 pathway can be functionally inactivated in sporadic breast cancer, suggesting that the pool of patients with defects in homologous recombinational repair is larger than initially expected. Citation Format: Simon N. Powell. Connections in the BRCA1-BRCA2 pathway of homologous recombination: Implications for breast cancer development and treatment [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY28-02