Atm-haploinsufficiency enhances susceptibility to carcinogen-induced mammary tumors.
Ataxia-telangiectasia (A-T), which is due to mutations in the ATM gene, is a rare autosomal recessive genomic instability syndrome characterized by radiosensitivity and predisposition to cancer. Epidemiological studies have suggested that relatives of A-T patients (A-T carriers) have increased risks of developing breast cancer. We propose that increased breast cancer risks in A-T carriers may be due to exposure to various environmental carcinogens and/or dietary consumption. To test this hypothesis, we treated a congenic strain of Atm+/- mice with DMBA (7,12-dimethylbenz(alpha)anthracene), a mammary carcinogen, and observed mammary tumor incidence. It was found that Atm+/- mice have a 2-fold increase, as well as early onset, in mammary tumor incidence relative to wild-type mice (P<0.005). The increased mammary tumor development is correlated with a 3-fold increase in the development of mammary dysplasia in Atm+/- compared with wild-type mice (P<0.05). We also found that Ras signaling pathway was not activated in DMBA-induced mammary tumors irrespective of the Atm status. At the cellular level, Atm-haploinsufficiency confers increased cellular stress manifested by an increased p53 expression and a slightly enhanced survival of mammary epithelial cells in response to radiation. Our results demonstrate that Atm heterozygotes are predisposed to mammary tumor development and support the hypothesis that exposure to environmental carcinogens contributes to the increased rate of breast cancer development in A-T carriers. Given that 1% of the general population are ATM heterozygotes (A-T carriers), this study has great implications in breast cancer development in this population.
Lu
Shu
S
Karmanos Cancer Institute, Department of Biochemistry and Molecular Biology, Wayne State University, School of Medicine, 110 E. Warren Avenue, Detroit, MI 48201, USA.
Shen
Kate
K
Wang
Yaolin
Y
Santner
Steven J
SJ
Chen
Jie
J
Brooks
S C
SC
Wang
Y Alan
YA
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics; D002273:Carcinogens / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004785:Environmental Pollutants / Q000494:pharmacology; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000517:prevention & control*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012307:Risk Factors; D015398:Signal Transduction; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D002273:Carcinogens; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004785:Environmental Pollutants; D025521:Tumor Suppressor Proteins; D015127:9,10-Dimethyl-1,2-benzanthracene; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases