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Xrcc2 modulates spontaneous and radiation-induced tumorigenesis in Apcmin/+ mice
Jackie W Haines1, Margaret R Coster, Julie Adam
1Health Protection Agency, Centre for Radiation, Chemical and Environmental Hazards, Chilton, Oxfordshire OX11 0RQ, United Kingdom. jackie.haines@hpa.org.uk
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.
Insights
Reduced DNA repair gene XRCC2 levels lower spontaneous tumor risk but increase radiation-induced cancer in mice. This suggests XRCC2
Area of Science:
- Genetics
- Cancer Biology
- DNA Repair Mechanisms
Background:
- XRCC2 is crucial for homologous recombination DNA repair.
- Apc(min/+) mice are a model for intestinal cancer.
- The role of XRCC2 in tumorigenesis and radiation response is not fully understood.
Purpose of the Study:
- To investigate the impact of Xrcc2 deficiency on spontaneous and radiation-induced tumor development in Apc(min/+) mice.
- To determine if Xrcc2 haploinsufficiency affects tumor progression and genomic instability.
Main Methods:
- Adult Apc(min/+) mice, wild-type or heterozygous for Xrcc2 deficiency, were subjected to sham or X-irradiation.
- Tumor incidence and multiplicity in mammary glands and intestines were assessed.
- Loss of heterozygosity analysis was performed on tumor samples.
Main Results:
- Xrcc2 haploinsufficiency reduced spontaneous mammary and intestinal tumor incidence in Apc(min/+) mice.
- However, Xrcc2 heterozygous mice showed a significantly greater increase in mammary and intestinal tumors following irradiation.
- Increased loss of heterozygosity was observed in intestinal tumors from Xrcc2 heterozygous mice.
Conclusions:
- XRCC2 haploinsufficiency lowers spontaneous tumor burden in a mouse model of intestinal cancer.
- Reduced XRCC2 levels exacerbate the tumorigenic effects of ionizing radiation, indicating a complex role in cancer development.
- These findings highlight the dual role of DNA repair pathways in cancer prevention and radiation sensitivity.
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