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Elevated Breast Cancer Risk in Irradiated BALB/c Mice Associates with Unique Functional Polymorphism of the Prkdc (DNA-dependent Protein Kinase Catalytic Subunit) Gene¹

Department of Radiation Oncology, The University of Texas Medical Branch, Galveston, Texas 77555 [Y. Y., M. M., R. Z., R. L. U.]; Department of Radiological Health Sciences, Colorado State University, Fort Collins, Colorado 80523 [R. O., R. L. U.]; Department of Experimental Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 [M. M. W., S. L.]; and National Radiological Protection Board, Chilton, Didcot, Oxon OX11 0RQ, United Kingdom [A. S., R. C.]

Female BALB/c mice are unusually radiosensitive and more susceptible than C57BL/6 and other tested inbred mice to ionizing radiation (IR)-induced mammary tumors. This breast cancer susceptibility is correlated with elevated susceptibility for mammary cell transformation and genomic instability following irradiation. In this study, we report the identification of two BALB/c strain-specific polymorphisms in the coding region of Prkdc, the gene encoding the DNA-dependent protein kinase catalytic subunit, which is known to be involved in DNA double-stranded break repair and post-IR signal transduction. First, we identified an A G transition at base 11530 resulting in a Met Val conversion at codon 3844 (M3844V) in the phosphatidylinositol 3-kinase domain upstream of the scid mutation (Y4046X). Second, we identified a C T transition at base 6418 resulting in an Arg Cys conversion at codon 2140 (R2140C) downstream of the putative leucine zipper domain. This unique Prkdc^BALB variant gene is shown to be associated with decreased DNA-dependent protein kinase catalytic subunit activity and with increased susceptibility to IR-induced genomic instability in primary mammary epithelial cells. The data provide the first evidence that naturally arising allelic variation in a mouse DNA damage response gene may associate with IR response and breast cancer risk.

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