ESTROGEN AND MNU SYNERGISM IN CARCINOGENESIS

大鼠低剂量注射N-甲基-N-亚硝脲(NMU) 雌激素背景显示较高的初始修复06- 甲基鸟嘌呤和较低的NMU诱导的成瘤率。 这些观察结果表明，更快的06-MeGua速率 在致癌物质暴露的早期阶段，修复是重要的， 有可能降低乳腺癌的发病率。此外， 雌激素对DNA烷基化和修复作用的研究进展 在细胞动力学的背景下可以提供额外的洞察力 关于NMU诱导乳腺的生化机制 腺癌的发生。 在建议书的第4-6年中，我们将1)确定 细胞动力学对乳腺易感性的影响 端芽(TEB)到N-甲基-N-亚硝脲(NMU) 在发情前期、发情期和发情间期用药后 放射自显影方法；2)表征06-甲基鸟嘌呤- 乳腺组织中DNA转甲基酶的表达 有发情周期相关的数量差异 乳腺上皮06-甲基鸟嘌呤-DNA转甲基酶 活动；3)使用去卵巢的麦角隐亭治疗53至55- 以1日龄大鼠为模型系统，检测06-甲基鸟嘌呤-6-甲基鸟嘌呤-2-甲基鸟嘌呤-2-甲基鸟嘌呤-2-甲基鸟嘌呤-2-甲基鸟嘌呤-2-甲基鸟嘌呤-2-甲基鸟嘌呤-2，4-甲基鸟嘌呤-2，4-甲基鸟嘌呤-2，4-甲基鸟嘌呤-2，6-甲基鸟嘌呤-2，6-甲基鸟嘌呤-2，4-甲基鸟嘌呤-2，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4， DNA转甲基酶仅在一定剂量的雌激素作用下可被诱导 和时间依赖的方式；4)确定乳房 卵巢切除对腺癌生长和反应的预测 A)NMU诱导的细胞周期动力学改变，b)时间 TEB增殖和c)核雌激素受体的差异 NMU时乳腺上皮细胞(ERN)含量 注射。 如果认为这些研究提供了一种方法来 理解雌激素作用的潜在机制(S) 致癌物诱发乳腺上皮细胞转化的研究 细胞，以及随后的乳腺肿瘤生物学。

Rats injected with N-methyl-N-nitrosourea (NMU) on a low estrogen background demonstrate a higher initial repair of 06- methylguanine and lower rates of NMU-induced tumorigenesis. These observations imply that a more rapid rate of 06-meGua repair is important in the early stages of carcinogen exposure, potentially reducing the incidence of mammary cancer. Further, elucidation of the effect of estrogen on DNA alkylation and repair in the context of cell kinetics may provide additional insight regarding the biochemical mechanism of NMU-induced mammary gland carcinogenesis. During years 4-6 of the proposal, we will 1) determine the influence of cell kinetics on the susceptibility of the mammary terminal end bud (TEB) to N-methyl-N-nitrosourea (NMU) following administration on proestrus, estrus and diestrus using an autoradiographic approach; 2) characterize 06-methylguanine- DNA transmethylase in mammary gland and determine whether there are estrous cycle associated quantitative differences in mammary epithelial 06-methylguanine-DNA transmethylase activity; 3) use ovariectomized ergocryptine-treated 53 to 55- day-old rats as a model system to test whether 06-methylguanine- DNA transmethylase is inducible solely with estrogen in a dose and time dependent manner; 4) determine if mammary adenocarcinoma growth and response ovariectomy is predicted by a) NMU-induced alterations of cell cycle kinetics, b) temporal differences in TEB proliferation, and c) nuclear estrogen receptor (ERN) content of mammary epithelial cells at the time of NMU injection. If is suggested that these studies provide an approach toward understanding the mechanism underlying the effect(s) of estrogen on carcinogen-induced transformation of mammary epithelial cells, and subsequent mammary tumor biology.