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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Mice with the CHEK2~* 1100delC SNP are predisposed to cancer with a strong gender bias
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Mice with the CHEK2~* 1100delC SNP are predisposed to cancer with a strong gender bias

机译：CHEK2〜* 1100delC SNP的小鼠易患性别偏见的癌症

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摘要

The CHEK2 kinase (Chk2 in mouse) is a member of a DNA damage response pathway that regulates cell cycle arrest at cell cycle checkpoints and facilitates the repair of dsDNA breaks by a recombination-mediated mechanism. There are numerous variants of the CHEK2 gene, at least one of which, CHEK2*1100delC (SNP), associates with breast cancer. A mouse model in which the wild-type Chk2 has been replaced by a Chk2~*1100delC allele was tested for elevated risk of spontaneous cancer and increased sensitivity to challenge by a carcinogenic compound. Mice homozygous for Chk2~*1100delC produced more tumors than wild-type mice, whereas heterozygous mice were not statistically different. When fractionated by gender, however, homozygous and heterozygous mice developed spontaneous tumors more rapidly and to a far greater extent than wild-type mice, indicative of a marked gender bias in mice harboring the variant allele. Consistent with our previous data showing elevated genomic instability in mouse embryonic fibroblasts (MEFs) derived from mice homozygous for Chk2~*1100delC, the level of Cdc25A was elevated in heterozygous and homozygous MEFs and tumors. When challenged with the carcinogen 7,12-dimethylbenz[a]anthracene, all mice, regardless of genotype, had a reduced lifespan. Latency for mammary tumori-genesis was reduced significantly in mice homozygous for Chk2~*1100delC but unexpectedly increased for the development of lymphomas. An implication from this study is that individuals who harbor the variant CHEK2~*1100delC allele not only are at an elevated risk for the development of cancer but also that this risk can be further increased as a result of environmental exposure.
机译：CHEK2激酶（小鼠中的Chk2）是DNA损伤反应途径的成员，该途径调节细胞周期检查点的细胞周期停滞，并通过重组介导的机制促进dsDNA断裂的修复。 CHEK2基因有多种变体，CHEK2 * 1100delC（SNP）中的至少一种与乳腺癌有关。测试了其中野生型Chk2已被Chk2〜* 1100delC等位基因替代的小鼠模型，其自发性癌症的风险增加，并且对致癌化合物的攻击敏感性增强。 Chk2〜* 1100delC纯合的小鼠比野生型小鼠产生更多的肿瘤，而杂合的小鼠没有统计学差异。然而，当按性别进行分馏时，纯合和杂合小鼠比野生型小鼠更迅速且自发地发展自发性肿瘤，这表明在携带变异等位基因的小鼠中存在明显的性别偏见。与我们先前的数据显示，纯合的Chk2〜* 1100delC小鼠来源的小鼠胚胎成纤维细胞（MEF）的基因组不稳定性升高，在杂合和纯合的MEF和肿瘤中Cdc25A的水平升高。当用致癌物7,12-二甲基苯并[a]蒽攻击时，所有小鼠，无论基因型如何，寿命都缩短。对于Chk2〜* 1100delC纯合的小鼠，乳腺肿瘤发生的潜伏期显着降低，但对于淋巴瘤的发生却出乎意料地增加。这项研究的结果是，携带CHEK2〜* 1100delC等位基因变异的个体不仅罹患癌症的风险增高，而且由于暴露于环境中，这种风险还会进一步增加。

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    El Mustapha Bahassi; Susan B. Robbins; Moying Yin; Gregory P. Boivin; Raoul Kuiper; Harry van Steeg; Peter J. Stambrook;

  • 作者单位

    Departments of Molecular Genetics and Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267;

    Departments of Molecular Genetics and Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267;

    Departments of Molecular Genetics and Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267;

    Laboratory Animal Resources, Wright State University, Dayton, OH 45435;

    Laboratory for Health Protection Research, National Institute of Public Health and the Environment, PO Box 1, 3720BA Bilthoven, The Netherlands;

    Laboratory for Health Protection Research, National Institute of Public Health and the Environment, PO Box 1, 3720BA Bilthoven, The Netherlands;

    Departments of Molecular Genetics and Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    cancer predisposition; Cdc25A; polymorphism;

    机译：癌症易感性Cdc25A;多态性;

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