Abstract CN05-04: Opportunities for targeting homologous recombination in human cancers.

Abstract BRCA2 mediates homologous recombination (HR) via its direct interaction with Rad51. 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. 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 BRCA1, PALB2 or BRCA2 deficiency, whereas there is no impact on cell growth in wild-type cells. The frequency of both spontaneous and double-strand break-induced homologous recombination, plus ionizing radiation induced Rad51 foci, decreased when Rad52 was depleted in BRCA2-deficient cells, with no effect in BRCA2-complemented cells. The observation that Rad52-inactivation is synthetic lethal with BRCA2 makes Rad52 a target for therapy in these tumors. The BRCA1-BRCA2 pathway can be functionally inactivated in sporadic breast cancer, perhaps as frequently as 20% of cases, suggesting that the pool of patients with defects in homologous recombinational repair is larger than initially expected. The functional assessment of defects in homologous recombination was assessed by ionizing-radiation (ex-vivo exposure) induced Rad51 foci and confirmed by characteristic patterns of array comparative genomic hybridization. The inactivation of the BRCA1-BRCA2 pathway allows the use of specific therapies designed to exploit the defects in DNA repair. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr CN05-04.