title: Atm heterozygous deficiency enhances development of mammary carcinomas in p53 heterozygous knockout mice.
abstract: BACKGROUND
  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 x 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 x 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Graduate school of Agriculture and Biological Sciences, Osaka Prefecture University, Osaka, Japan. umesako@riast.osakafu-u.ac.jp
authors.forename: Seiichi
authors.initials: S
authors.lastname: Umesako
authors.forename: Kae
authors.initials: K
authors.lastname: Fujisawa
authors.forename: Sayoko
authors.initials: S
authors.lastname: Iiga
authors.forename: Nobuko
authors.initials: N
authors.lastname: Mori
authors.forename: Masahiro
authors.initials: M
authors.lastname: Takahashi
authors.forename: Doo-Pyo
authors.initials: DP
authors.lastname: Hong
authors.forename: Chang-Woo
authors.initials: CW
authors.lastname: Song
authors.forename: Satomi
authors.initials: S
authors.lastname: Haga
authors.forename: Syunsuke
authors.initials: S
authors.lastname: Imai
authors.forename: Otsura
authors.initials: O
authors.lastname: Niwa
authors.forename: Masaaki
authors.initials: M
authors.lastname: Okumoto
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002277:Carcinoma / Q000235:genetics* / Q000503:physiopathology* / Q000517:prevention & control; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D005260:Female; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D019656:Loss of Heterozygosity; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000503:physiopathology* / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009381:Neoplasms, Radiation-Induced; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology; D012307:Risk Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000502:physiology
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases