Atm heterozygosity cooperates with loss of Brca1 to increase the severity of mammary gland cancer and reduce ductal branching

The role of homozygous ataxia telangiectasia mutated (ATM) mutations in familial and sporadic forms of cancer is well established, but the contribution of ATM heterozygosity to mammary gland and other cancers has been controversial. To test the effect of Atm heterozygosity on mammary gland cancer, mice with complete loss of exon 11 of Brca-1 specifically in mammary epithelium (Brea1-MG-Delta ex11) were studied in either Atm heterozygous or Atm wild-type backgrounds. Targeted deletion of Brcal in mammary epithelium resulted in carcinomas and adenocarcinomas of varying histology with long (> 9 months) latency. Latency to tumorigenesis was found to be unchanged in the Brca1-MG Delta ex11;Atm heterozygous mice compared with Brca1-MG Delta exll;Atm wild-type mice. However, the mice displayed variable tumor severity and differences in mammary tissue development. Mammary tumors from Brea1-MG-Delta ex11;-4tm heterozygous mice were anaplastic and undifferentiated in all 20 tumors tested, whereas tumors from mice that were Brea1-MG-Delta ex11 but wild-type for Atm displayed variable histologic profiles, with some anaplastic tumors and other differentiated and less invasive tumor types. Previously reported developmental defects for Brea1-deficient mice were also observed in our model with and without Atm heterozygosity, but Brea1-MG-Delta ex11 Atm heterozygous mice displayed decreased ductal branching during puberty, a phenotype that was not observed in Brea1-MG-Delta ex11; Atm wild-type mice. Our results provide evidence that Atm heterozygosity influences severity of mammary gland tumors in the Brca1-MG-Delta ex11 tumor-prone mouse and suggest that this mutation leads to a newly characterized developmental defect during glandular maturation.