Radiation induces genomic instability and mammary ductal dysplasia in Atm heterozygous mice.
Radiation induces genomic instability and mammary ductal dysplasia in Atm heterozygous mice.
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辐射会导致 Atm 杂合子小鼠基因组不稳定和乳腺导管发育不良。
DOI：
10.1038/sj.onc.1204589
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发表时间：
2001
期刊：
影响因子：
--
通讯作者：
Ullrich,RL
中科院分区：
文献类型：
--
作者：
Weil,MM;Kittrell,FS;Yu,Y;McCarthy,M;Zabriskie,RC;Ullrich,RL
共济失调-毛细血管扩张症（AT）是由ATM基因的两个缺陷拷贝遗传引起的遗传综合征，其特征包括辐射敏感性和癌症易感性。流行病学研究表明，尽管ATM（AT杂合子）单拷贝缺陷的女性在临床上表现正常，但她们患乳腺癌的相对风险可能会增加。她们是否因医疗暴露于电离辐射而增加了辐射诱发乳腺癌的风险尚不清楚。我们已经使用了一个小鼠模型的AT调查的影响，一个单一的缺陷Atm等位基因，小鼠同源的ATM，对乳腺上皮细胞的敏感性辐射诱导的转化。在这里，我们报告说，乳腺上皮细胞与一个副本的ATM截断PI-3激酶结构域辐射小鼠易受辐射诱导的基因组不稳定性，并产生了10%的发病率发育不良的乳腺导管移植到同基因受体，而细胞从ATM+/+小鼠是稳定的，只形成正常的导管。由于辐射诱导的导管发育不良是乳腺癌的前兆，结果表明，AT杂合性增加了对放射性乳腺癌的易感性，在这个小鼠模型系统。
Ataxia-telangiectasia (AT) is a genetic syndrome resulting from the inheritance of two defective copies of the ATM gene that includes among its stigmata radiosensitivity and cancer susceptibility. Epidemiological studies have demonstrated that although women with a single defective copy of ATM (AT heterozygotes) appear clinically normal, they may never the less have an increased relative risk of developing breast cancer. Whether they are at increased risk for radiation-induced breast cancer from medical exposures to ionizing radiation is unknown. We have used a murine model of AT to investigate the effect of a single defective Atm allele, the murine homologue of ATM, on the susceptibility of mammary epithelial cells to radiation-induced transformation. Here we report that mammary epithelial cells from irradiated mice with one copy of Atm truncated in the PI-3 kinase domain were susceptible to radiation-induced genomic instability and generated a 10% incidence of dysplastic mammary ducts when transplanted into syngenic recipients, whereas cells from Atm+/+ mice were stable and formed only normal ducts. Since radiation-induced ductal dysplasia is a precursor to mammary cancer, the results indicate that AT heterozygosity increases susceptibility to radiogenic breast cancer in this murine model system.