The effect of NBS1 heterozygous inactivating mutation in a model of 7,12-dimethylbenz[a]anthracene-induced carcinogenesis in mice

Abstract

BACKGROUND: The creation of new experimental models carrying various heterozygous inactivating mutations in DNA repair genes and their carcinogenesis studies could expand our understanding of the spectrum of possible neoplasms that patients with such mutations are at risk of developing.

AIM: The study of the effect of NBS1 inactivating heterozygous mutation (с.1971insT, p.Arg658Stop) in a model of 7,12-dimethylbenz[a]anthracene (DMBA) induced carcinogenesis in mice.

MATERIALS AND METHODS: Carcinogenesis was induced in 2-month-old female mice with and without NBS1 heterozygous mutation by intragastric administration of 7,12-DMBA (dose of 50 mg/kg once a week, for 8 weeks) on a high-fat diet. Lifetime observation was conducted, and parameters of lifespan and carcinogenesis were evaluated.

RESULTS: NBS1 inactivating heterozygous mutation had no significant effect on the incidence of tumor pathology induced by 7,12-DMBA, but somewhat accelerated the rate of tumor development and, consequently, the death of animals. The presence of the mutation increased the sensitivity to carcinogen toxic effect, which was expressed in a statistically significant increase in death rate (by 35%) in the early stages of the study. The mean lifespan in female NBS1 mutant mice was reduced by 14% compared to mutation-free animals.

CONCLUSION: Carrying NBS1 inactivating heterozygous mutation (с.1971insT, p.Arg658Stop) worsens the prognosis of survival in the model of chemically induced 7,12-DMBA carcinogenesis in mice.

Keywords

NBS1 / heterozygous mutation / 7,12-DMBA / carcinogenesis / mice

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Funding

Российский Научный Фонд (грант)Russian Science Foundation (grant)(22-25-00569)

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