Elevated breast cancer risk in irradiated BALB/c mice associates with unique functional polymorphism of the Prkdc (DNA-dependent protein kinase catalytic subunit) gene

Yongjia Yu, R. Okayasu, M. M. Weil, A. Silver, M. McCarthy, R. Zabriskie, S. Long, R. Cox, R. L. Ullrich

Research output: Contribution to journalArticle

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Abstract

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 PrkdcBALB 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.

Original languageEnglish (US)
Pages (from-to)1820-1824
Number of pages5
JournalCancer Research
Volume61
Issue number5
StatePublished - Mar 1 2001

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DNA-Activated Protein Kinase
Ionizing Radiation
Catalytic Domain
Breast Neoplasms
Genomic Instability
Codon
Genes
Breast
Phosphatidylinositol 3-Kinase
Leucine Zippers
Double-Stranded DNA Breaks
DNA Damage
Signal Transduction
Epithelial Cells
Mutation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Elevated breast cancer risk in irradiated BALB/c mice associates with unique functional polymorphism of the Prkdc (DNA-dependent protein kinase catalytic subunit) gene. / Yu, Yongjia; Okayasu, R.; Weil, M. M.; Silver, A.; McCarthy, M.; Zabriskie, R.; Long, S.; Cox, R.; Ullrich, R. L.

In: Cancer Research, Vol. 61, No. 5, 01.03.2001, p. 1820-1824.

Research output: Contribution to journalArticle

Yu, Y, Okayasu, R, Weil, MM, Silver, A, McCarthy, M, Zabriskie, R, Long, S, Cox, R & Ullrich, RL 2001, 'Elevated breast cancer risk in irradiated BALB/c mice associates with unique functional polymorphism of the Prkdc (DNA-dependent protein kinase catalytic subunit) gene', Cancer Research, vol. 61, no. 5, pp. 1820-1824.
Yu, Yongjia ; Okayasu, R. ; Weil, M. M. ; Silver, A. ; McCarthy, M. ; Zabriskie, R. ; Long, S. ; Cox, R. ; Ullrich, R. L. / Elevated breast cancer risk in irradiated BALB/c mice associates with unique functional polymorphism of the Prkdc (DNA-dependent protein kinase catalytic subunit) gene. In: Cancer Research. 2001 ; Vol. 61, No. 5. pp. 1820-1824.
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