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Atm heterozygous deficiency enhances development of mammary carcinomas in p53 heterozygous knockout mice
INTRODUCTION: Ataxia-telangiectasia is an autosomal-recessive disease that affects neuro-immunological functions, associated with increased susceptibility to malignancy, chromosomal instability and hypersensitivity to ionizing radiation. Although ataxia-telangiectasia mutated (ATM) heterozygous defi...
Autores principales: | , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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BioMed Central
2005
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1064114/ https://www.ncbi.nlm.nih.gov/pubmed/15642165 http://dx.doi.org/10.1186/bcr968 |
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author | Umesako, Seiichi Fujisawa, Kae Iiga, Sayoko Mori, Nobuko Takahashi, Masahiro Hong, Doo-Pyo Song, Chang-Woo Haga, Satomi Imai, Syunsuke Niwa, Otsura Okumoto, Masaaki |
author_facet | Umesako, Seiichi Fujisawa, Kae Iiga, Sayoko Mori, Nobuko Takahashi, Masahiro Hong, Doo-Pyo Song, Chang-Woo Haga, Satomi Imai, Syunsuke Niwa, Otsura Okumoto, Masaaki |
author_sort | Umesako, Seiichi |
collection | PubMed |
description | INTRODUCTION: Ataxia-telangiectasia is an autosomal-recessive disease that affects neuro-immunological functions, associated with increased susceptibility to malignancy, chromosomal instability and hypersensitivity to ionizing radiation. Although ataxia-telangiectasia mutated (ATM) heterozygous deficiency has been proposed to increase susceptibility to breast cancer, some studies have not found excess risk. In experimental animals, increased susceptibility to breast cancer is not observed in the Atm heterozygous deficient mice (Atm(+/-)) carrying a knockout null allele. In order to determine the effect of Atm heterozygous deficiency on mammary tumourigenesis, we generated a series of Atm(+/- )mice on the p53(+/- )background with a certain predisposition to spontaneous development of mammary carcinomas, and we examined the development of the tumours after X-irradiation. METHODS: BALB/cHeA-p53(+/- )mice were crossed with MSM/Ms-Atm(+/- )mice, and females of the F(1 )progeny ([BALB/cHeA × MSM/Ms]F(1)) with four genotypes were used in the experiments. The mice were exposed to X-rays (5 Gy; 0.5 Gy/min) at age 5 weeks. RESULTS: We tested the effect of haploinsufficiency of the Atm gene on mammary tumourigenesis after X-irradiation in the p53(+/- )mice of the BALB/cHeA × MSM/Ms background. The singly heterozygous p53(+/- )mice subjected to X-irradiation developed mammary carcinomas at around 25 weeks of age, and the final incidence of mammary carcinomas at 39 weeks was 31% (19 out of 61). The introduction of the heterozygous Atm knockout alleles into the background of the p53(+/- )genotype significantly increased the incidence of mammary carcinoma to 58% (32 out of 55) and increased the average number of mammary carcinomas per mouse. However, introduction of Atm alleles did not change the latency of development of mammary carcinoma. CONCLUSION: Our results indicate a strong enhancement in mammary carcinogenesis by Atm heterozygous deficiency in p53(+/- )mice. Thus, doubly heterozygous mice represent a useful model system with which to analyze the interaction of heterozygous genotypes for p53, Atm and other genes, and their effects on mammary carcinogenesis. |
format | Text |
id | pubmed-1064114 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2005 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-10641142005-03-11 Atm heterozygous deficiency enhances development of mammary carcinomas in p53 heterozygous knockout mice Umesako, Seiichi Fujisawa, Kae Iiga, Sayoko Mori, Nobuko Takahashi, Masahiro Hong, Doo-Pyo Song, Chang-Woo Haga, Satomi Imai, Syunsuke Niwa, Otsura Okumoto, Masaaki Breast Cancer Res Research Article INTRODUCTION: Ataxia-telangiectasia is an autosomal-recessive disease that affects neuro-immunological functions, associated with increased susceptibility to malignancy, chromosomal instability and hypersensitivity to ionizing radiation. Although ataxia-telangiectasia mutated (ATM) heterozygous deficiency has been proposed to increase susceptibility to breast cancer, some studies have not found excess risk. In experimental animals, increased susceptibility to breast cancer is not observed in the Atm heterozygous deficient mice (Atm(+/-)) carrying a knockout null allele. In order to determine the effect of Atm heterozygous deficiency on mammary tumourigenesis, we generated a series of Atm(+/- )mice on the p53(+/- )background with a certain predisposition to spontaneous development of mammary carcinomas, and we examined the development of the tumours after X-irradiation. METHODS: BALB/cHeA-p53(+/- )mice were crossed with MSM/Ms-Atm(+/- )mice, and females of the F(1 )progeny ([BALB/cHeA × MSM/Ms]F(1)) with four genotypes were used in the experiments. The mice were exposed to X-rays (5 Gy; 0.5 Gy/min) at age 5 weeks. RESULTS: We tested the effect of haploinsufficiency of the Atm gene on mammary tumourigenesis after X-irradiation in the p53(+/- )mice of the BALB/cHeA × MSM/Ms background. The singly heterozygous p53(+/- )mice subjected to X-irradiation developed mammary carcinomas at around 25 weeks of age, and the final incidence of mammary carcinomas at 39 weeks was 31% (19 out of 61). The introduction of the heterozygous Atm knockout alleles into the background of the p53(+/- )genotype significantly increased the incidence of mammary carcinoma to 58% (32 out of 55) and increased the average number of mammary carcinomas per mouse. However, introduction of Atm alleles did not change the latency of development of mammary carcinoma. CONCLUSION: Our results indicate a strong enhancement in mammary carcinogenesis by Atm heterozygous deficiency in p53(+/- )mice. Thus, doubly heterozygous mice represent a useful model system with which to analyze the interaction of heterozygous genotypes for p53, Atm and other genes, and their effects on mammary carcinogenesis. BioMed Central 2005 2004-12-10 /pmc/articles/PMC1064114/ /pubmed/15642165 http://dx.doi.org/10.1186/bcr968 Text en Copyright © 2004 Umesako et al., licensee BioMed Central Ltd. |
spellingShingle | Research Article Umesako, Seiichi Fujisawa, Kae Iiga, Sayoko Mori, Nobuko Takahashi, Masahiro Hong, Doo-Pyo Song, Chang-Woo Haga, Satomi Imai, Syunsuke Niwa, Otsura Okumoto, Masaaki Atm heterozygous deficiency enhances development of mammary carcinomas in p53 heterozygous knockout mice |
title | Atm heterozygous deficiency enhances development of mammary carcinomas in p53 heterozygous knockout mice |
title_full | Atm heterozygous deficiency enhances development of mammary carcinomas in p53 heterozygous knockout mice |
title_fullStr | Atm heterozygous deficiency enhances development of mammary carcinomas in p53 heterozygous knockout mice |
title_full_unstemmed | Atm heterozygous deficiency enhances development of mammary carcinomas in p53 heterozygous knockout mice |
title_short | Atm heterozygous deficiency enhances development of mammary carcinomas in p53 heterozygous knockout mice |
title_sort | atm heterozygous deficiency enhances development of mammary carcinomas in p53 heterozygous knockout mice |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1064114/ https://www.ncbi.nlm.nih.gov/pubmed/15642165 http://dx.doi.org/10.1186/bcr968 |
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