ESTROGEN AND MNU SYNERGISM IN CARCINOGENESIS

大鼠注射N-甲基-N-亚硝基脲（NMU）， 雌激素背景显示06- 甲基鸟嘌呤和更低的NMU诱导的肿瘤发生率。 这些观察结果意味着， 修复在致癌物暴露的早期阶段是重要的， 潜在地降低乳腺癌的发病率。 此外，本发明还 雌激素对DNA烷基化和修复作用的阐明 在细胞动力学的背景下， 关于NMU诱导乳腺癌的生化机制， 腺体癌变 在提案的第4-6年，我们将1）确定 细胞动力学对乳腺癌易感性的影响 末端芽（TEB）转化为N-甲基-N-亚硝基脲（NMU） 在发情前期、发情期和间情期使用 放射自显影方法; 2）表征06-甲基鸟嘌呤- DNA甲基转移酶，并确定是否 发情周期相关的数量差异， 乳腺上皮06-甲基鸟嘌呤-DNA转移甲基酶 活性; 3）使用切除卵巢的麦角隐亭处理的53至55- 一日龄大鼠作为模型系统，以测试06-甲基鸟嘌呤- DNA甲基转移酶仅在一定剂量的雌激素下可诱导 和时间依赖的方式; 4）确定是否乳房 腺癌生长和卵巢切除术的反应是预测 a）NMU诱导的细胞周期动力学改变，B）时间 TEB增殖的差异，和c）核雌激素受体 (ERN)NMU时乳腺上皮细胞的含量 注射 如果建议，这些研究提供了一种方法， 了解雌激素作用的机制 致癌物诱导的乳腺上皮细胞转化 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.