Xrcc2 Modulates Spontaneous and Radiation-Induced Tumorigenesis in Apcmin/+ Mice

Abstract XRCC2 has an important role in repair of DNA damage by homologous recombination. Adult Apcmin/+ (min, multiple intestinal neoplasia) mice, wild-type or heterozygous for Xrcc2 deficiency, were sham-irradiated or 2-Gy X-irradiated. Spontaneous mammary and intestinal tumor incidences are lower in Apcmin/+ Xrcc2+/− mice than in Apcmin/+ Xrcc2+/+ mice (mammary tumors: 14% and 38%, respectively, χ2 P = 0.03; intestinal adenomas in mice reaching full life span: 108.6 and 130.1, respectively, t-test P = 0.005). Following irradiation, the increase in mammary tumors was greatest in female mice heterozygous for Xrcc2 (7.25 ± 0.50-fold in Apcmin/+ Xrcc2+/− mice compared with 2.57 ± 0.35-fold in Apcmin/+ Xrcc2+/+ mice; t-test P < 0.001). The increase in intestinal tumor multiplicity following irradiation was significantly greater in Apcmin/+ Xrcc2+/− mice (Apcmin/+ Xrcc2+/−, 4.14 ± 0.05-fold, versus Apcmin/+ Xrcc2+/+, 3.30 ± 0.05-fold; t-test P < 0.001). Loss of heterozygosity of all chromosome 18 markers was greater in intestinal tumors from Apcmin/+ Xrcc2+/− mice than in tumors from Apcmin/+ Xrcc2+/+ mice. These findings indicate that Xrcc2 haploinsufficiency reduces spontaneous tumor incidence on an Apcmin/+ background but increases the tumorigenic response to radiation. Mol Cancer Res; 8(9); 1227–33. ©2010 AACR.