Inhibitory Effects of Toremifene on N-Methyl-N-nitrosourea and Estradiol-17β-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)-1α, estrogen receptor (ER)-α mRNAs and corresponding proteins induced by estradiol-l7β (E₂), in the uteri of the ovariectomized mice. Expression of ER-β 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, E₂ diet (5 ppm) plus TOR (0.2 mg/30 g body weight, subcutaneously, every four weeks); group 2, E₂ diet alone; group 3, basal diet plus TOR. Group 4 served as the control. TOR treatment decreased the incidence of MNU and E₂-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-1α expression induced by E₂. Such suppressive effects of TOR may be related to the decreased ER-α and increased ER-β expressions.