Research article

Atm heterozygous deficiency enhances development of mammary carcinomas in p53 heterozygous knockout mice

Seiichi Umesako¹ , Kae Fujisawa² , Sayoko Iiga¹ , Nobuko Mori^1,3 , Masahiro Takahashi¹ , Doo-Pyo Hong¹ , Chang-Woo Song⁴ , Satomi Haga⁵ , Syunsuke Imai⁶ , Otsura Niwa⁷ and Masaaki Okumoto^1,3

¹Graduate school of Agriculture and Biological Sciences, Osaka Prefecture University, Osaka, Japan

²Research Institute of New Medicines, Shionogi Pharmaceutical Co., Osaka, Japan

³Research Institute for Advanced Science and Technology, Osaka Prefecture University, Osaka, Japan

⁴Korea Research Institute of Chemical Technology, Taejon, Korea

⁵Department of Anatomy, Nara Medical University, Nara, Japan

⁶Nara Prefecture Institute for Hygiene and Environment, Nara, Japan

⁷Radiation Biology Center, Kyoto University, Kyoto, Japan

author email corresponding author email

Breast Cancer Res 2005, 7:R164-R170doi:10.1186/bcr968

Published:	10 December 2004

Abstract

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 F₁ progeny ([BALB/cHeA × MSM/Ms]F₁) 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.