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.