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 Apc min/+ (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 Apc min/+ Xrcc2 +/− mice than in Apc min/+ Xrcc2 +/+ mice (mammary tumors: 14% and 38%, respectively, χ 2 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 Apc min/+ Xrcc2 +/− mice compared with 2.57 ± 0.35-fold in Apc min/+ Xrcc2 +/+ mice; t-test P < 0.001). The increase in intestinal tumor multiplicity following irradiation was significantly greater in Apc min/+ Xrcc2 +/− mice (Apc min/+ Xrcc2 +/− , 4.14 ± 0.05-fold, versus Apc min/+ 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 Apc min/+ Xrcc2 +/− mice than in tumors from Apc min/+ Xrcc2 +/+ mice. These findings indicate that Xrcc2 haploinsufficiency reduces spontaneous tumor incidence on an Apc min/+ background but increases the tumorigenic response to radiation. Mol Cancer Res; 8(9); 1227-33. ©2010 AACR.

shRNA-Mediated XRCC2 Gene Knockdown Efficiently Sensitizes Colon Tumor Cells to X-ray Irradiation in Vitro and in Vivo

“…A recent study showed that the incidence of spontaneous breast and intestinal tumorigenesis was higher in XRCC2 +/+ mice than in XRCC2 +/− animals [22], implicating a possible role for XRCC2 in affecting tumor cells’ radiosensitivity. In the present study, we found that the expression of XRCC2 protein was elevated in colon cancer cells compared with normal cells.…”

Dose-rate effects in radiation biology and radiation protection

“…There is evidence that genes such as Prkdc and Xrcc2, involved in the non-homologous end joining and homologous recombination repair pathways, respectively, modify radiation cancer risk in mouse models, and there is a degree of tissue specificity (e.g. Degg et al, 2003;Haines et al, 2010Haines et al, , 2015. Although DNA repair genes have not been commonly identified in screens for radiation cancer risk modifiers, some repair-related genes have been found to modify risk in humans, most notably in the case of ATM and radiogenic breast cancer (e.g.…”

Haploinsufficiency in mouse models of DNA repair deficiency: modifiers of penetrance

“…However, when crossed with the APCmin mouse model, Haines et al found that Xrcc2 modifies the impact of APC mutagenesis [53]. These data are interesting, though not inconsistent with the above described studies, in that the effect of Xrcc2 gene dosage (i.e., protective or detrimental) depends upon the specific experimental conditions.…”

“…These data are interesting, though not inconsistent with the above described studies, in that the effect of Xrcc2 gene dosage (i.e., protective or detrimental) depends upon the specific experimental conditions. Xrcc2 heterozygosity protects from the spontaneous intestinal tumorigenesis induced by the APC mutation, but enhances IR-induced tumorigenicity in this same APC model [53]. It is difficult to reconcile such data without further experimental evidence.…”