Carcinogenesis Advance Access originally published online on January 7, 2006
Carcinogenesis 2006 27(4):848-855; doi:10.1093/carcin/bgi302
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Atm-haploinsufficiency enhances susceptibility to carcinogen-induced mammary tumors
1 Karmanos Cancer Institute, 2 Department of Biochemistry and Molecular Biology, 3 Department of Pathology, Wayne State University, School of Medicine, 110 E. Warren Avenue, Detroit, MI 48201, USA, 4 Department of Tumor Biology, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA and 5 Department of Mathematics, University of Massachusetts, Boston, MA 02215, USA
* To whom correspondence should be addressed. Tel: +1 313 833 0715; Fax: +1 313 831 7518; E-mail: wangya{at}kci.wayne.edu
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(
)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.