International Mammalian Genome Society

The 15th International Mouse Genome Conference (2001)


Dr. Michael Weil
M.D. Anderson Cancer Center
Department of Experimental Radiation Oncology -66
1515 Holcombe Blvd.
TX 77030

Co-Authors: 1)Yu Y, 2)Okayasu R, 3)Cox R, 3)Silver A, 2)Ullrich RL
Institutions: 1)University of Texas Medical Branch, 2)Colorado State University, 3)National Radiological Protection Board

Exposure to ionizing radiation leads to an increased risk for breast cancer, but the role of interindividual genetic variation in determining that risk in humans is unknown.  We are using murine models of radiogenic breast cancer to identify candidate genes for further study in humans, and to validate candidate genes identified in other systems.  Inbred mouse strains differ in their susceptibility to radiogenic mammary tumors. Using BALB/c mice (susceptible) and C57BL/6 (resistant), we have linked polymorphisms in Prkdc to susceptibility to radiation-induced mammary tumorigenesis. Prkdc encodes DNA-PKcs, a protein involved in the repair of radiation-induced DNA double-strand breaks (DSB).  The BALB/c variant of DNA-PKcs contains two amino acid substitutions that are associated with low levels of DNA-PKcs protein, decreased DSB repair capacity, and cytogenetic instability following irradiation.  These findings suggest that a genetic association study of human PRKDC variants in patients with suspected radiation-induced breast cancers may be productive.  We have taken the opposite approach with ATM.  Germline mutations in ATM are suspected of increasing breast cancer risk, but epidemiological studies have been contradictory. We have demonstrated increased susceptibility to radiation-induced ductal dysplasia and mammary epithelial cell cytogenetic instability in mice engineered to have one defective copy of Atm.  These endpoints are precursors to breast cancer.

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