乳腺癌易感基因CHEK2 Y390C 突变致基因组不稳定的机制研究

Cell cycle checkpoint kinase 2 (CHEK2) participates in the regulation of cell cycle checkpoints and DNA repair following DNA damage. Allelic variants of CHEK2 contribute to an elevated risk for breast cancer. Our previous studies showed that germline CHEK2 Y390C variants was associated with early-onset breast cancer, however, the effects of CHEK2 Y390C variant on cell cycle and DNA damage repair remains to be corroborated. In this study, we firstly tend to generate knock-in mice that carry CHEK2 Y390C polymorphism and then to be crossed with transgenic mice expression MMTV-PyT to generate mammary tumor spontaneous formation. Polyploidy and an increase in DNA double strand breaks of the CHEK2 Y390C cells are indicated as signs of spontaneous genomic instability. Accordingly, mouse embryo fibroblasts (MEFs) and mammary endothelial cells derived from these mice are isolated. Alterations of CHEK2 mRNA expression, cell cycle profile, and activation of components of the DNA damage response signaling pathway of the CHEK2 Y390C cells subjected to ionizing radiation are evaluated. This research, having a very promising value in the clinical application, will help us resolve whether individuals with such susceptibility alleles are rendered more susceptible to breast cancer than the general population when exposure to DNA damage.

细胞周期检验点激酶2（CHEK2）是参与DNA损伤修复的重要激酶，与乳腺癌的遗传易感有重要联系。遗传性乳腺癌特点除家族聚集外，早发性是其主要临床特征。我们前期研究发现胚系CHEK2 Y390C与早发性乳腺癌明显相关，而Y390C对细胞周期和DNA修复功能的意义不明。本研究首先建立CHEK2 Y390C基因敲入小鼠，回交转基因小鼠MMTV-PyT获得自发性乳腺癌小鼠模型。将细胞周期中多倍体出现以及DNA双链断裂增加作为Y390C致基因组不稳定的特点。据此，给予电离辐射后，观察Y390C等位基因状态不同的鼠胚胎性成纤维细胞和小鼠乳腺内皮细胞CHEK2 mRNA表达、细胞周期和DNA损伤后修复能力的影响。本研究通过建立基因敲入小鼠模型，有助于深入了解CHEK2 Y390C的携带者在外界DNA损伤暴露的环境下，是否增加乳腺癌患病风险，具有一定临床应用价值。

细胞周期检验点激酶 2（CHEK2）是参与 DNA 损伤修复的重要激酶，与乳腺癌的遗传易感有重要联系。 遗传性乳腺癌特点除家族聚集外，早发性是其主要临床特征。 我们前期研究发现胚系 CHEK2 Y390C 与早发性乳腺癌明显相关，而 Y390C 对细胞周期和 DNA 修复功能的意义不明。本研究首先建立 CHEK2 Y390C 基因敲入小鼠，回交转基因小鼠 MMTV-PyT获得自发性乳腺癌小鼠模型。将细胞周期中多倍体出现以及 DNA 双链断裂增加作为 Y390C 致基因组不稳定的特点。据此，给予电离辐射后，观察 Y390C 等位基因状态不同的鼠胚胎性成纤维细胞和小鼠乳腺内皮细胞 CHEK2 mRNA 表达、细胞周期和 DNA 损伤后修复能力的影响。本研究通过建立基因敲入小鼠模型，有助于深入了解 CHEK2 Y390C 的携带者在外界 DNA 损伤暴露的环境下，是否增加乳腺癌患病风险，具有一定临床应用价值。

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