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

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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.

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作者简介

Maria Yurova

N.N. Petrov National Medical Research Centre of Oncology

编辑信件的主要联系方式.
Email: yumarni@gmail.com
ORCID iD: 0000-0003-3589-5871
SPIN 代码: 3497-5175

Cand.  Sci. (Bio.)

俄罗斯联邦, 68 Leningradskaya street, Pesochny, 197758 Saint Petersburg

Alexey Golubev

N.N. Petrov National Medical Research Centre of Oncology

Email: lxglbv@rambler.ru
ORCID iD: 0000-0002-2129-6205
SPIN 代码: 2871-0779

Cand.  Sci. (Bio.)

俄罗斯联邦, 68 Leningradskaya street, Pesochny, 197758 Saint Petersburg

Elena Fedoros

N.N. Petrov National Medical Research Centre of Oncology

Email: elenafedoros@gmail.com
ORCID iD: 0000-0002-2426-9843
SPIN 代码: 3302-1384

Cand.  Sci. (Bio.)

俄罗斯联邦, 68 Leningradskaya street, Pesochny, 197758 Saint Petersburg

Irina Tumanyan

N.N. Petrov National Medical Research Centre of Oncology

Email: itumanyan@mail.ru
ORCID iD: 0000-0002-8926-1519
SPIN 代码: 1165-4685
俄罗斯联邦, 68 Leningradskaya street, Pesochny, 197758 Saint Petersburg

Yulia Von

N.N. Petrov National Medical Research Centre of Oncology

Email: takeo_yuki@mail.ru
ORCID iD: 0000-0002-5161-5940
SPIN 代码: 8621-1112
俄罗斯联邦, 68 Leningradskaya street, Pesochny, 197758 Saint Petersburg

Alexander Semenov

N.N. Petrov National Medical Research Centre of Oncology

Email: genesem7@gmail.com
ORCID iD: 0000-0002-5190-0629
SPIN 代码: 4301-8679

MD, Cand.  Sci. (Med.)

俄罗斯联邦, 68 Leningradskaya street, Pesochny, 197758 Saint Petersburg

Ekaterina Otradnova

N.N. Petrov National Medical Research Centre of Oncology

Email: katya.otradnova@mail.ru
ORCID iD: 0009-0003-0158-1820
SPIN 代码: 9861-0730
俄罗斯联邦, 68 Leningradskaya street, Pesochny, 197758 Saint Petersburg

Evgeny Imyanitov

N.N. Petrov National Medical Research Centre of Oncology

Email: evgeny@imyanitov.spb.ru
ORCID iD: 0000-0003-4529-7891
SPIN 代码: 1909-7323

MD, Dr. Sci. (Med.), Professor, Corresponding Member of the Russian Academy of Sciences

俄罗斯联邦, 68 Leningradskaya street, Pesochny, 197758 Saint Petersburg

参考

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2. Fig. 1. Dynamics of body weight in female NBS1 heterozygous mutant mice (BALB/c/F1) in a model of 7,12-dimethylbenz[a]anthracene-induced carcinogenesis. Data presented as «mean ± standard error of the mean». * — difference is statistically significant, р <0.05; NBS1insT — mutation in NBS1 gene present; wt — wild type.

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3. Fig. 2. Survival curves of female NBS1 heterozygous mutant mice (BALB/c/F1) in a model of 7,12-dimethylbenz[a]anthracene-induced carcinogenesis. NBS1insT — mutation in NBS1 gene present; wt — wild type.

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4. Fig. 3. Morphological study of mammary carcinoma sections. a — squamous cell keratinizing carcinoma; b — metastasis to the lung. Hematoxylin-eosin, ×100.

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5. Fig. 4. Morphological study of lymphoma sections. a — lymphoma lesion of the lung; b — lymphoma lesion of the kidney. Hematoxylin-eosin, ×100.

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6. Fig. 5. Mortality curves of female tumor-bearing mice (BALB/c/F1) carrying NBS1 heterozygous mutations in a model of 7,12-dimethylbenz[a]anthracene-induced carcinogenesis. NBS1insT — mutation in NBS1 gene present; wt — wild type.

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