Inhibitory effects of toremifene on N-methyl-N-nitrosourea and estradiol-17beta-induced endometrial carcinogenesis in mice.
Short- and long-term experiments were designed to determine the effects of toremifene (TOR) on estrogen-related endometrial carcinogenesis in mice. In the short-term experiment, a single low dose of TOR (0.2 mg / 30 g body weight) decreased expression of c-fos, interleukin (IL)-1alpha, estrogen receptor (ER)-alpha mRNAs and corresponding proteins induced by estradiol-17beta (E(2)), in the uteri of the ovariectomized mice. Expression of ER-beta mRNA was increased by the TOR treatment, compared with the control. In the long-term experiment, 106 female ICR mice were given N-methyl-N-nitrosourea (MNU) into their uterine corpora. The animals were divided into four groups as follows: group 1, E(2) diet (5 ppm) plus TOR (0.2 mg / 30 g body weight, subcutaneously, every four weeks); group 2, E(2) diet alone; group 3, basal diet plus TOR. Group 4 served as the control. TOR treatment decreased the incidence of MNU and E(2)-induced endometrial adenocarcinoma and atypical hyperplasia at the termination of the experiment (30 weeks after the start). These results suggest that TOR exerts preventive effects against estrogen-related endometrial carcinogenesis in mice, through the suppression of c-fos as well as IL-1alpha expression induced by E(2). Such suppressive effects of TOR may be related to the decreased ER-alpha and increased ER-beta expressions.
Niwa
Kenji
K
Department of Obstetrics and Gynecology, Gifu University School of Medicine, Gifu 500-8705. kniwa@cc.gifu-u.ac.jp
Hashimoto
Midori
M
Lian
Zenglin
Z
Gao
Jingchun
J
Tagami
Keiko
K
Yokoyama
Yasuhiro
Y
Mori
Hideki
H
Tamaya
Teruhiko
T
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D015139:Blotting, Southern; D002273:Carcinogens; D016889:Endometrial Neoplasms / Q000139:chemically induced* / Q000517:prevention & control; D004958:Estradiol; D047628:Estrogen Receptor alpha; D005260:Female; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000096:biosynthesis; D008770:Methylnitrosourea; D051379:Mice; D008813:Mice, Inbred ICR; D010053:Ovary / Q000473:pathology; D016133:Polymerase Chain Reaction; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D011960:Receptors, Estrogen / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D017312:Toremifene / Q000494:pharmacology*; D014599:Uterus / Q000473:pathology
D018931:Antineoplastic Agents, Hormonal; D002273:Carcinogens; D047628:Estrogen Receptor alpha; D007375:Interleukin-1; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D004958:Estradiol; D008770:Methylnitrosourea; D017312:Toremifene