ESTROGEN AND NMU SYNERGISM IN CARCINOGENESIS

大鼠注射n -甲基-n -亚硝基脲（NMU）后

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.