Methylguanine methyltransferase activity deficiency in immature rat mammary epithelial cells parallels increased carcinogenic susceptibility
Methylguanine methyltransferase activity deficiency in immature rat mammary epithelial cells parallels increased carcinogenic susceptibility
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DOI：
10.1002/mc.20131
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发表时间：
2005-11-01
影响因子：
4.6
通讯作者：
Gould, MN
中科院分区：
文献类型：
--
作者：
Ariazi, JL;Haag, JD;Gould, MN
青春期前的乳房比成熟的乳房更容易受到电离辐射的致癌作用，并可能受到香烟烟雾和烷基化化疗药物的影响。性未成熟（3周龄）Fischer 344大鼠的乳腺上皮细胞（MEC）比成熟（8周龄）大鼠对N-亚硝基-N-甲基脲（NMU）的致癌、致死和致突变作用更敏感。本文报告的工作是为了更好地定义乳腺对NMU的年龄特异性易感性。使用碱性彗星试验，它被发现，MEC从未成熟的，但不成熟的大鼠表现出增加单链DNA断裂或碱不稳定的病变后2小时NMU治疗。Hoechst染色显示细胞凋亡不是导致细胞凋亡的原因。甲基鸟嘌呤甲基转移酶（MGMT）的抑制不影响未成熟的MEC，但引起成熟的MEC重演对NMU的未成熟反应。MGMT活性的直接测量显示，未成熟的MEC是显着缺乏MGMT活性相对于成熟的MEC。在所有检测的器官中，MEC具有最低的MGMT活性。未成熟的肾脏，NMU治疗后优先发展成肾细胞瘤，也显示出显着低于成熟的肾脏MGMT活性。这些结果表明，MGMT活性的年龄相关差异可能在大鼠乳腺癌和肾癌发生的年龄差异易感性中发挥重要作用，并认为将这些研究扩展到人类的重要性。它们还为研究青春期前女孩暴露于烷化剂（人类在香烟烟雾、饮食和化疗中暴露于烷化剂）作为乳腺癌的潜在起始事件提供了机制基础。(c)2005 Wiley-Liss，Inc.
The prepubertal breast is more susceptible than the mature breast to the carcinogenic effects of ionizing radiation, and potentially to cigarette smoke and alkylating chemotherapeutics. Mammary epithelial cells (MECs) from sexually immature (3-week (wk)-old) Fischer 344 rats were more sensitive than mature (8-wk-old) rats to the carcinogenic, lethal, and mutagenic effects of N-nitroso-N-methylurea (NMU). The work reported here was undertaken to better define this age-specific susceptibility of the mammary gland to NMU. Using the alkaline comet assay, it was found that MECs from immature but not mature rats displayed an increase in single-strand DNA breaks or alkali-labile lesions 2 h following NMU treatment. Hoechst staining indicated apoptosis was not responsible for the increase. inhibition of methylguanine methyltransferase (MGMT) did not affect immature MECs but caused mature MECs to recapitulate the immature response to NMU. Direct measurement of MGMT activity revealed that immature MECs are significantly deficient in MGMT activity relative to mature MECs. MECs had the lowest MGMT activity of all organs tested. Immature kidneys, which preferentially developed nephroblastomas after NMU treatment, also displayed significantly lower MGMT activity than mature kidneys. These results suggest that age-related differences in MGMT activity may play a significant role in age-differential susceptibility to rat mammary gland and kidney carcinogenesis, and argue the importance of extending these studies to humans. They also provide a mechanistic basis for studying, as potentially initiating events in breast cancer, exposures of prepubertal girls to alkylating agents, to which humans are exposed in cigarette smoke, the diet, and as chemotherapy. (c) 2005 Wiley-Liss, Inc.