Atm-haploinsufficiency enhances susceptibility to carcinogen-induced mammary tumors.
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AbstractAtaxia-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.
CitationCarcinogenesis 2006, 27 (4):848-855
DescriptionBiomarkers of exposure & effect:: validationBiomarker: A-T carriersExposure/effect represented: DMBAStudy type (in vitro, animals, humans): Atm male miceMode of exposure (if in vivo) (acute, chronic, root of exposure): administration by oral gavageMethod of analysis: PCRDose-response: Nearly twice as many Atm heterozygotes developed mammary tumors (64.7%) as the wild-type mice (37.5%). RR for DMBA-induced mammary tumors is 1.7 for Atm heterozygotesAtm heterozygotes developed mammary tumors with an average onset of 189 days compared with 229 days for wild-type mice (P < 0.005 by log-rank test). KEYWORDS CLASSIFICATION: 9,10-Dimethyl-1,2-benzanthracene;Animals;Biology;Breast Neoplasms;Carcinogens;Cell Cycle;Cell Cycle Proteins;DNA-Binding Proteins;etiology;Environmental Pollutants;Female;genetics;Genetic Predisposition to Disease;Heterozygote;Mammary Neoplasms,Animal;mechanisms of carcinogenesis;Mice;Molecular Biology;pharmacology;prevention & control;Protein-Serine-Threonine Kinases;Proteins;Research;Risk Factors;Signal Transduction;Survival Analysis;Tumor Suppressor Proteins.