Radiation induces genomic instability and mammary ductal dysplasia in Atm heterozygous mice

Ataxia-telangiectasia (AT) is a genetic syndrome resulting from the inherit ance of two defective copies of the ATM gene that includes among its stigma ta radiosensitivity and cancer susceptibility. Epidemiological studies have demonstrated that although women with a single defective copy of ATM (AT h eterozygotes) appear clinically normal, they may never the less have an inc reased relative risk of developing breast cancer. Whether they are at incre ased risk for radiation-induced breast cancer from medical exposures to ion izing radiation is unknown. We have used a murine model of AT to investigat e the effect of a single defective Atm allele, the murine homologue of ATM, on the susceptibility of mammary epithelial cells to radiation-induced tra nsformation. Here we report that mammary epithelial cells from irradiated m ice with one copy of Atm truncated in the PI-3 kinase domain were susceptib le to radiation-induced genomic instability and generated a 10% incidence o f dysplastic mammary ducts when transplanted into syngenic recipients, wher eas cells from Atm(+/+) mice were stable and formed only normal ducts. Sinc e radiation-induced ductal dysplasia is a precursor to mammary cancer, the results indicate that AT heterozygosity increases susceptibility to radioge nic breast cancer in this murine model system.