Data from <i>Atm</i> Heterozygosity Cooperates with Loss of <i>Brca1</i> to Increase the Severity of Mammary Gland Cancer and Reduce Ductal Branching

Abstract

<div>Abstract<p>The role of homozygous ataxia telangiectasia mutated (<i>ATM</i>) mutations in familial and sporadic forms of cancer is well established, but the contribution of <i>ATM</i> heterozygosity to mammary gland and other cancers has been controversial. To test the effect of <i>Atm</i> heterozygosity on mammary gland cancer, mice with complete loss of exon 11 of <i>Brca1</i> specifically in mammary epithelium (<i>Brca1</i>-MG-Δex11) were studied in either <i>Atm</i> heterozygous or <i>Atm</i> wild-type backgrounds. Targeted deletion of <i>Brca1</i> 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 <i>Brca1</i>-MG-Δex11;<i>Atm</i> heterozygous mice compared with <i>Brca1</i>-MG-Δex11;<i>Atm</i> wild-type mice. However, the mice displayed variable tumor severity and differences in mammary tissue development. Mammary tumors from <i>Brca1</i>-MG-Δex11;<i>Atm</i> heterozygous mice were anaplastic and undifferentiated in all 20 tumors tested, whereas tumors from mice that were <i>Brca1</i>-MG-Δex11 but wild-type for <i>Atm</i> displayed variable histologic profiles, with some anaplastic tumors and other differentiated and less invasive tumor types. Previously reported developmental defects for <i>Brca1</i>-deficient mice were also observed in our model with and without <i>Atm</i> heterozygosity, but <i>Brca1</i>-MG-Δex11;<i>Atm</i> heterozygous mice displayed decreased ductal branching during puberty, a phenotype that was not observed in <i>Brca1</i>-MG-Δex11;<i>Atm</i> wild-type mice. Our results provide evidence that <i>Atm</i> heterozygosity influences severity of mammary gland tumors in the <i>Brca1</i>-MG-Δex11 tumor-prone mouse and suggest that this mutation leads to a newly characterized developmental defect during glandular maturation.</p></div>