Abstract 2377: Variation in the BRCT1 domain of the DNA repair gene XRCC1 delays invasive breast cancer in mice

Abstract

Abstract The breast cancer susceptibility protein BRCA1 C-terminal (BRCT) domain coordinates protein interactions in DNA repair and cell cycle control, and comprises over 100 member proteins. One of these, XRCC1, is involved in base excision repair and single strand break repair. In order to investigate the role of the XRCC1-BRCT1 domain in breast cancer, we generated a mouse line with a variation of leucine (L) from arginine (R) at position 360, and crossed it with PyMT transgenic mice with a highly penetrant metastatic breast cancer phenotype. PyMT mice with advanced tumors expressing the L360R variant (N=20) had an average tumor volume of 360±57 mm3 compared to an average tumor volume of 730±69 mm3 for PyMT/wild type littermates (N=20), significant at p less than 0.01. In addition, the L360R variant was associated with a significant decrease in metastatic foci in the lungs of PyMT mice, an increase in tumor cell apoptosis as measured by caspase 3 immunohistochemistry, a decrease in tumor cell proliferation as measured by ki-67 immunohistochemistry, and a decrease in PARP binding as determined by NADH depletion. These preliminary observations suggest that the XRCC1/BRCT1 domain is involved in invasive breast cancer, and that genetic variation of this domain can suppress the invasive phenotype by decreasing tumor cell proliferation and increasing apoptosis of tumor cells possibly in association with altered PARP binding and activity. The XRCC1 L360R mouse is a promising animal model to further investigate the potential of targeting the XRCC1/BRCT1 domain for adjunctive treatment of invasive breast cancer. 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 2377. doi:10.1158/1538-7445.AM2011-2377