The natural hormone 17 beta-estradiol (E2) induces tumors in various organs of rats, mice, and hamsters. In humans, slightly elevated circulating estrogen levels caused either by increased endogenous hormone production or by therapeutic doses of estrogen medications increase breast or uterine cancer risk. Several epigenetic mechanisms of tumor induction by this hormone have been proposed based on its lack of mutagenic activity in bacterial and mammalian cell test systems. More recent evidence supports a dual role of estrogen in carcinogenesis as a hormone stimulating cell proliferation and as a procarcinogen inducing genetic damage. Tumors may be initiated by metabolic conversion of E2 to 4-hydroxyestradiol catalyzed by a specific 4-hydroxylase (CYP1B1) and by further activation of this catechol to reactive semiquinone/quinone intermediates. Several types of direct and indirect free radical-mediated DNA damage are induced by E2, 4-hydroxyestradiol, or its corresponding quinone in cell-free systems, in cells in culture, and/or in vivo. E2 also induces various chromosomal and genetic lesions including aneuploidy, chromosomal aberrations, gene amplification, and microsatellite instability in cells in culture and/or in vivo and gene mutations in several cell test systems. These data suggest that E2 is a weak carcinogen and weak mutagen capable of inducing genetic lesions with low frequency. Tumors may develop by hormone receptor-mediated proliferation of such damaged cells.
Estrogen is a known risk factor in human breast cancer. In rodent models, estradiol has been shown to induce tumors in those tissues in which this hormone is predominantly converted to the catechol metabolite 4-hydroxyestradiol by a specific 4-hydroxylase enzyme, whereas tumors fail to develop in organs in which 2-hydroxylation predominates. We have now found that microsomes prepared from human mammary adenocarcinoma and fibroadenoma predominantly catalyze the metabolic 4-hydroxylation of estradiol (ratios of 4-hydroxyestradiol/2-hydroxyestradiol formation in adenocarcinoma and fibroadenoma, 3.8 and 3.7, respectively). In contrast, microsomes from normal tissue obtained either from breast cancer patients or from reduction mammoplasty operations expressed comparable estradiol 2-and 4-hydroxylase activities (corresponding ratios, 1.3 and 0.7, respectively). An elevated ratio of 4-/2-hydroxyestradiol formation in neoplastic mammary tissue may therefore provide a useful marker of benign or malignant breast tumors and may indicate a mechanistic role of 4-hydroxyestradiol in tumor development.The prolonged exposure of women to high estrogen levels has been associated with an elevated incidence of breast cancer (1, 2). Thus, risk factors for this disease include high serum or urinary estrogen concentrations (3-5), the early onset of menstruation, and late menopause (1, 2). In rodent models, in which the natural hormone estradiol (E2) induces tumors, there is a differential formation of the two catechol metabolites, 2-and 4-hydroxyestradiol (2-and 4-OH-E2, respectively), which correlates with the organ's resistance or susceptibility to estrogen-induced carcinogenesis. Thus, in Syrian hamster kidney, CD-1 mouse uterus, and rat pituitary, all susceptible to tumor induction by E2 (6-8), 4-OH-E2 formation predominates, whereas in these rodents' livers, where tumors are not induced under these conditions, 2-hydroxylation of E2 predominates (9-11). By analogy, in human uterine myoma, 4-hydroxylation of E2 by a distinct and specific estrogen 4-hydroxylase activity predominates over that in surrounding myometrium and over 2-hydroxylation in either tissue (12).Moreover, in human MCF-7 breast cancer cells, the formation of 4-OH-E2 is catalyzed by cytochrome P450 IB1 and is inducible by 2,3,7,8-tetrachlorodibenzo-p-dioxin, a common environmental pollutant (13). In contrast, microsomal preparations from human liver or placenta catalyze the oxidation of E2 mainly to 2-OH-E2 with <-20% 4-OH-E2 formation (12,(14)(15)(16)(17). This hepatic formation of catecholestrogen metabolites is catalyzed mainly by the cytochrome P450 IIIA family of enzymes, which generates -85% 2-OH-E2 and, in addition, -15% 4-OH-E2 due to a lack of enzyme specificity (14-19).
In western society, the causes of several cancers--including breast, endometrium, ovary, liver, and prostate--have been linked to inappropriate and/or prolonged exposure to synthetic or endogenous steroidal hormones. In this review, we discuss the mechanisms of estrogen carcinogenesis with a focus on estrogen metabolism to 16 alpha-hydroxy estrone and 2- and 4-hydroxy catechol estrogens and the potential effects of these metabolites in vitro and in vivo on hamster liver and kidney and rat liver carcinogenesis models. The examples demonstrate that the parent compounds and their metabolites cause both nongenotoxic cell proliferative effects as well as direct and indirect genotoxic effects, which illustrates the complex nature of estrogen carcinogenesis. These effects, in combination with the metabolic state of the tissue and the timing of its exposure, may determine the cell type (organ) of tumor development and the severity of disease.
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