Is Estradiol a Genotoxic Mutagenic Carcinogen?

Abstract

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.

Protective roles of quinone reductase and tamoxifen against estrogen-induced mammary tumorigenesis

“…8-hydroxydeoxyguanine, 8-OH-dG) and permanent mutation if not repaired (Liehr, 2000). Glutathione-S-transferase (GST) detoxifies these quinones by conjugation with glutathione, and catechol O-methyltransferase (COMT) detoxifies the hydroxy-catecholestrogens by methylation (Liehr, 2000). We provide data in this report that support the involvement of quinone reductase (QR) in the metabolism of catechol estrogen quinones.…”

“…It has been hypothesized that initiation results from induction of DNA damage by estrogen metabolites and in concert with pre-existing lesions, whereas upregulation of mitogenic genes through the estrogen receptor (ER) may facilitate progression (Liehr, 2000).…”

“…Redox cycling, involving quinone and unstable semiquinone interconversions, causes hydroxyl radical formation that can lead to hydroxylated bases (e.g. 8-hydroxydeoxyguanine, 8-OH-dG) and permanent mutation if not repaired (Liehr, 2000). Glutathione-S-transferase (GST) detoxifies these quinones by conjugation with glutathione, and catechol O-methyltransferase (COMT) detoxifies the hydroxy-catecholestrogens by methylation (Liehr, 2000).…”

Role of hormone cofactors in the human papillomavirus-induced carcinogenesis of the uterine cervix

“…Estrogen has a wellknown mitogenic activity (Liehr, 2000) which may be amplified by viral oncoproteins. It has been shown to stimulate the proliferation of human keratinocytes by promoting the expression of cyclin D2 which induces G1 to S phase progression in the cell cycle (Kanda and Watanabe, 2004).…”

Inhibition of 17β-HSD1: SAR of bicyclic substituted hydroxyphenylmethanones and discovery of new potent inhibitors with thioether linker

“…[1] They exert their effects by transactivation of the respective nuclear receptors, [2] although also non-genomic effects are discussed. [3] However, these steroidal sex hormones are also involved in the genesis and the progression of diseases.…”