A New Hypothesis for Uterine Carcinogenesis: A Pathway Driven by Modulation of Estrogen Metabolism through Cytochrome P450 Induction in the Rat Liver

Abstract

Estrogen dependence is generally accepted as a cue for mammary and uterine carcinogenesis, but recently estrogen metabolite or catechol-estrogen driven pathways have also come under consideration. Endometrial adenocarcinoma is a leading cause of cancer death in women. Although the cancer is rare in most strains of rodents, it develops spontaneously and can be readily induced in the Donryu rat strain, with many morphological, endocrinological and molecular similarities to the human case. The goal of this review is to weigh the hypothesis for a new pathway for endometrial carcinogenesis driven by modulation of estrogen metabolism through cytochrome P450 enzyme induction using data from the Donryu rat model. To test our hypothesis, indole-3-carbinol (I3C), an active ingredient of cruciferous vegetable, was selected, since it induces cytochrome P450 enzymes in the liver which impact on hydroxylation of estrogens. In uterotrophic assays using ovariectomized rats, neither 500 ppm nor 2000 ppm of I3C in the diet caused any estrogenic or anti-estrogenic activity. However, in our 2-stage rat uterine cancer model, dietary I3C and subcutaneous injection of 4-hydroxyestradiol (4HE), one of hydroxylation metabolites of 17β-estradiol (E2), elevated both incidences of uterine adenocarcinomas and multiplicities of uterine proliferative lesions. I3C treatment increased mRNAs for 1A1, 1A2 and 1B1 in the liver, reflecting the distribution of corresponding enzymes immunohistochemically demonstrated. In the uterus, only CYP 1A1 mRNA was increased by the treatment, without reflecting protein expression. In the liver, I3C consistently elevated estradiol 2 and 4 hydroxylation. These results indicate that modulation of estrogen metabolism, particularly to increase 4HE through induction of CYP 1 in the liver, plays a crucial role in promoting effects of dietary I3C on endometrial adenocarcinoma development, providing support for our hypothesis of a new pathway for endometrial carcinogenesis in the rat.