Our long-term goal is to better understand the role that the ATM protein plays in suppression of breast cancer. ATM is a DNA damage-responsive protein kinase that is a critical component in the genome damage response system. ATM is mutated in the human disorder Ataxia-Telangiectasia (A-T), a cancer prone disorder, and like A-T patients, Atm-deficient mice also show a high predisposition to the development of hematological malignancy. While this observation adds to the evidence that ATM is an important tumor suppressor, it is unclear to what extent this protein plays in acting as a barrier to the development of other malignancies. A-T heterozygotes show an increased risk of developing breast cancer. Also, sporadic breast tumors often show reduced in ATM expression. Atm heterozygous mice show an elevated level of mammary tumors when challenged with carcinogens or mated into a tumor-prone genetic background. These facts lead us to hypothesize that ATM is a tumor suppressor critical to limiting breast cancer development. The goal of this R03 application is to develop and initially characterize a mouse line to test this supposition. Our study has 3 Specific Aims: 1) Develop a mouse line with disruption of the Atm gene specifically within the mammary epithelium. We outline a straightforward mating scheme to create the novel Atm conditional knockout (cKO) line using a recently established mouse line containing a """"""""floxed"""""""" ATM allele and commercially-available MMTV-cre mice. 2) Conduct a detailed morphological and molecular characterization of the mammary glands of Atm conditional knockout mice. We will study Atm cKO mammary glands during development, pregnancy and involution to fully characterize the role this protein plays in the biology of this organ. Further, we will determine the extent of diminished Atm expression in ATM cKO mammary glands. 3) Determine if Atm conditional knockout mice show increased mammary tumor incidence compared to controls. We will develop a colony of multiparous Atm cKO mice and determine if this line shows elevated rates of mammary tumors compared to normal controls. Development of the ATM cKO mouse line has great promise as a powerful tool in addressing the role of ATM as a barrier to breast carcinogenesis.
| Dyer, Lisa M; Kepple, Jessica D; Ai, Lingbao et al. (2017) ATM is required for SOD2 expression and homeostasis within the mammary gland. Breast Cancer Res Treat 166:725-741 |
| Alpay, Merve; Backman, Lindsey R F; Cheng, Xiaodong et al. (2015) Oxidative stress shapes breast cancer phenotype through chronic activation of ATM-dependent signaling. Breast Cancer Res Treat 151:75-87 |
