Effects of tamoxifen on endometrial carcinogenesis in mice.
Two experiments were conducted to determine the effect of tamoxifen (TAM) in mouse endometrium in comparison with that of 17beta-estradiol (E2). In a medium-term assay, TAM as well as E2 treatment semi-dose-dependently increased the levels of fos/jun mRNA and their oncoproteins (Fos/Jun). The long-term effect of TAM on mouse endometrial carcinogenesis was also examined in the following model. A total of 150 female ICR mice, 12-13 weeks of age, were used. Of these, 125 mice received an injection of N-methyl-N-nitosourea (MNU) solution (1 mg/100 g body weight) into their left uterine tube and saline into the right. One week later, they were divided into four groups: groups 1 (35 mice) and 2 (30 mice) were given 25 ppm and ppm E2-containing diet, respectively, while group 3 (30 mice) was fed 5 ppm TAM-containing diet. Group 5 (30 mice) was fed basal diet alone. The remaining 25 mice (group 4) received 5 ppm TAM-containing diet alone. At the termination of the experiment (30 weeks), endometrial carcinomas were confirmed to be present in the groups exposed to MNU. TAM increased the incidence of preneoplastic lesions of the endometrium, while E2 enhanced the occurrence of the carcinoma. No carcinomas were found in the group given TAM alone. In the ovaries, corpora lutea were lacking in most of the mice exposed to TAM, suggesting that the animals were not cycling. Such findings indicated that TAM has an enhancing effect on endometrial carcinogenesis in mice, probably via a mechanism involving overexpression of Fos/Jun proteins.
Department of Obstetrics & Gynecology, Gifu University School of Medicine.
K
K
Niwa
S
S
Morishita
M
M
Hashimoto
T
T
Itoh
J
J
Fujimoto
H
H
Mori
T
T
Tamaya
D000230:Adenocarcinoma / Q000139:chemically induced*; D000818:Animals; D002273:Carcinogens; D003043:Cocarcinogenesis; D016889:Endometrial Neoplasms / Q000139:chemically induced*; D004717:Endometrium / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000633:toxicity; D005260:Female; D006965:Hyperplasia; D008770:Methylnitrosourea; D051379:Mice; D008813:Mice, Inbred ICR; D010052:Ovariectomy; D016133:Polymerase Chain Reaction; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013629:Tamoxifen / Q000633:toxicity*
D002273:Carcinogens; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D013629:Tamoxifen; D004958:Estradiol; D008770:Methylnitrosourea