Elevated breast cancer risk in irradiated BALB/c mice associates with unique functional polymorphism of the Prkdc (DNA-dependent protein kinase catalytic subunit) gene.
Elevated breast cancer risk in irradiated BALB/c mice associates with unique functional polymorphism of the Prkdc (DNA-dependent protein kinase catalytic subunit) gene.
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发表时间：
2001-03
期刊：
影响因子：
11.2
通讯作者：
Yongjia Yu;R. Okayasu;Michael M. Weil;Andy Silver;Maureen McCarthy;Ryan C. Zabriskie;Scott Long;Roger Cox;Robert L. Ullrich
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作者：
Yongjia Yu;R. Okayasu;Michael M. Weil;Andy Silver;Maureen McCarthy;Ryan C. Zabriskie;Scott Long;Roger Cox;Robert L. Ullrich
雌性 BALB/c 小鼠对放射线异常敏感，并且比 C57BL/6 和其他测试的近交小鼠更容易受到电离辐射 (IR) 诱发的乳腺肿瘤的影响。这种乳腺癌易感性与放射后乳腺细胞转化和基因组不稳定性的易感性升高相关。在这项研究中，我们报告了 Prkdc 编码区中两个 BALB/c 菌株特异性多态性的鉴定，Prkdc 是编码 DNA 依赖性蛋白激酶催化亚基的基因，已知该基因参与 DNA 双链断裂修复和红外后信号转导。首先，我们鉴定了碱基 11530 处的 A --> G 转换，导致 scid 突变 (Y4046X) 上游磷脂酰肌醇 3-激酶结构域中密码子 3844 (M3844V) 处的 Met --> Val 转换。其次，我们确定了碱基 6418 处的 C --> T 转变，导致假定的亮氨酸拉链结构域下游密码子 2140 (R2140C) 处的 Arg --> Cys 转换。这种独特的 PrkdcBALB 变异基因被证明与 DNA 依赖性蛋白激酶催化亚基活性降低以及原代乳腺上皮细胞对 IR 诱导的基因组不稳定性的敏感性增加有关。这些数据提供了第一个证据，表明小鼠 DNA 损伤反应基因中自然产生的等位基因变异可能与 IR 反应和乳腺癌风险相关。
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.