Abstract
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 Brca1 specifically in mammary epithelium (Brca1-MG-Deltaex11) were studied in either Atm heterozygous or Atm wild-type backgrounds. Targeted deletion of Brca1 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-Deltaex11;Atm heterozygous mice compared with Brca1-MG-Deltaex11;Atm wild-type mice. However, the mice displayed variable tumor severity and differences in mammary tissue development. Mammary tumors from Brca1-MG-Deltaex11;Atm heterozygous mice were anaplastic and undifferentiated in all 20 tumors tested, whereas tumors from mice that were Brca1-MG-Deltaex11 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 Brca1-deficient mice were also observed in our model with and without Atm heterozygosity, but Brca1-MG-Deltaex11;Atm heterozygous mice displayed decreased ductal branching during puberty, a phenotype that was not observed in Brca1-MG-Deltaex11;Atm wild-type mice. Our results provide evidence that Atm heterozygosity influences severity of mammary gland tumors in the Brca1-MG-Deltaex11 tumor-prone mouse and suggest that this mutation leads to a newly characterized developmental defect during glandular maturation.
Highlights
Breast cancer is the most common nondermatologic cancer diagnosed in humans and the second leading cause of cancer deathNote: H
To analyze the possible effects that Atm heterozygosity may have during tumorigenesis in mammary tissue that lacks intact Brca1, mice carrying mutations for either Brca1 or Atm were mated to generate a compound genotype
We found that cyclin D1, cdc2, c-Myc, and erbB2 were all overexpressed in Brca1 exon 11–deficient mammary tumors of either Atm genotype compared with normal mammary tissues (Fig. 3)
Summary
When Crerecombinase was expressed from either the mouse mammary tumor virus long terminal repeat promoter (MMTV-LTR) or the whey acidic protein promoter, Brca was deleted in mammary epithelium [35] These mice displayed variable types of mammary carcinomas, commonly ductal and lobular carcinomas as well as more rare cases of squamous carcinomas, medullary carcinomas, and anaplastic carcinomas, all of which are found in human familial breast cancers [36, 37]. Cancers from both Atm and Brca knockouts display several obvious similarities, including diminished DNA damage response, cell cycle defects, and extensive genomic rearrangements These studies together suggest that there may be a link between Atm haploinsufficiency and loss of Brca that can be effectively investigated using the mouse as a model. We found that Atm haploinsufficiency resulted in absence of differentiated tumor types and increased invasiveness as well as reduced ductal branching in virgin mice, supporting a role for Atm in mammary gland tumorigenesis and development
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