Abstract 2807: Characterization and targeting BRIT1 deficiency in cancer
Authors: Yulong Liang, Hong Gao, Shiaw-Yih Lin, Kaiyi Li
Journal: Cancer Research (2011)

Abstract BRIT1 protein (also known as MCPH1) contains 3 BRCT domains which are conserved in BRCA1and other important molecules involved in DNA damage signaling, DNA repair, and tumor suppression. We identified BRIT1 mutations or aberrant expression in cancer patients including breast cancer and ovarian cancer. Our recent in vitro studies also suggest that BRIT1/MCPH1 functions as a novel key regulator in the DDR pathways. To investigate its physiological role and dissect the underlying mechanisms, we generated BRIT1−/− mice and identified its essential roles in both mitotic and meiotic homologous recombination (HR) DNA repair and in maintaining genomic stability. BRIT1−/− mice were infertile and meiotic HR was impaired with reduced foci formation of RAD51 or BRCA2. In addition, both BRIT1−/− mice and mouse embryonic fibroblasts (MEFs) were hypersensitive to gamma-irradiation. BRIT1−/− MEFs exhibited severe chromatid breaks. Notably, BRIT1 could bind to RAD51/BRCA2 complexes and that, in the absence of BRIT1, recruitment of RAD51 and BRCA2 to chromatin was reduced, indicating that BRIT1 is involved in mediating recruitment of RAD51/BRCA2 to the damage site and as a result, protect the genome from DNA damage. Furthermore, we found that BRIT1 deficiency could promote tumorigenesis in mice. We observed incidence of ovarian tumors in BRIT1−/− mice (1.5 to 2 year-old). By administering the carcinogen DMBA, BRIT1−/− mice were prone to develop breast tumors. Moreover, BRIT1 deficiency enhanced tumor susceptibility of p53−/− mice by generation of the double null (BRIT1−/−p53−/−) mice. BRIT1−/−p53−/− MEFs exhibited more aberrant chromatids than p53−/− MEFs and ectopic BRIT1 could rescue this aberration. IR-induced foci formation (IRIF) of RAD51/BRCA2 was impaired in the double null MEFs and ectopic BRIT1 restored IRIF of RAD51/BRCA2 in BRIT1−/−p53−/− MEFs, indicating BRIT1 participates in DNA repair via recruitment of the complex RAD51/BRCA2. Finally, given that BRIT1−/− cells exhibited defective HR DNA repair described above, we exploited PARP inhibitors to target the BRIT1-deficient cancers, and found that PARP inhibitor, olaparib could selectively kill the BRIT1-deficient breast cancer cells and MEFs. Currently, we are using mouse models to assess if the BRIT1-deficient tumor can be selectively suppressed by PARP inhibitors in vivo. Collectively, our unique knockout mouse model clearly demonstrates that BRIT1 is essential for maintaining genomic stability through mediating recruitment of RAD51/BRCA2 to the DNA damage site, and its deficiency causes defective HR DNA repair and promotes cancer development. Our data further indicate that targeting BRIT1 deficiency using PARP inhibitors may lead to novel and effective targeted therapies to treat BRIT1-deficient cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2807. doi:10.1158/1538-7445.AM2011-2807