Takeki Tsutsui1 and J. Carl Barrett2
1Department of Pharmacology, School of Dentistry at Tokyo, The Nippon Dental University, Tokyo, Japan; 2Environmental Carcinogenesis Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
Estrogens are clearly carcinogenic in humans and rodents but the mechanisms by which these hormones induce cancer are only partially understood. Stimulation of cell proliferation and gene expression by binding to the estrogen receptor is one important mechanism in hormonal carcinogenesis; however, estrogenicity is not sufficient to explain the carcinogenic activity of all estrogens because some estrogens are not carcinogenic. Estrogens are nonmutagenic in many assays but exhibit specific types of genotoxic activity under certain conditions. We have studied extensively the mechanisms by which estrogens induce neoplastic transformation in a model in vitro system and our findings are summarized in this review. 17ß-Estradiol (E2) and diethylstilbestrol (DES) and their metabolites induce morphological and neoplastic transformation of Syrian hamster embryo (SHE) cells that express no measurable levels of estrogen receptor. Treatment of the cells with E2 or DES fails to induce DNA damage, chromosome aberrations and gene mutations in SHE cells but results in numerical chromosome aberrations (aneuploidy) that could arise from microtubule disruption or disfunction of mitotic apparatus. Estrogen-induced genotoxicity is detected in cells following treatment with estrogen metabolites or following exogenous metabolic activation of estrogens. The estrogens induce DNA adduct formation that is detected by 32P-postlabeling. Both aneuploidy induction and DNA damage caused by DNA adduct formation correlate with the estrogen-induced cell transformation and may be important in hormonal carcinogenesis. We propose that multiple effects of estrogens acting together cause genetic alterations leading to cell transformation. -- Environ Health Perspect 105(Suppl 3):619-624 (1997)
Key words: estrogens, estrogen metabolites, cell transformation, genotoxicity
This paper was presented in part at the Workshop on Hormones, Hormone Metabolism, Environment, and Breast Cancer held 28-29 September 1995 in New Orleans, Louisiana. Manuscript received at EHP 6 June 1996; manuscript accepted 13 September 1996.
Address correspondence to Dr. J.C. Barrett, National Institute of Environmental Health Sciences, PO Box 12233, Research Triangle Park, NC 27709. Telephone: (919) 541-2992. Fax: (919) 541-7784. E-mail:barrett@niehs.nih.gov
Abbreviations used: DES, diethylstilbestrol;
-dienestrol, trans,trans-dienestrol; ß-dienestrol, cis,cis-dienestrol; DMS, dimethylstilbestrol; DM-DES, dimethoxydiethylstilbestrol; E1, estrone; E2, 17ß-estradiol; E3, estriol; HEX, hexestrol; MN, microcuclei; 8-OH-dG, 8-hydroxy-2´-deoxyguanosine; 16-OH E1, 16-hydroxyestrone; 2-OH E1, 2-hydroxyestrone; 2-OH E2, 2-hydroxyestradiol; 4-OH E2, 4-hydroxyestradiol; PMS, postmitochondrial supernatant; SHE, Syrian hamster embryo; TF-DES, tetrafluorodiethylstilbestrol; UDS, unscheduled DNA synthesis.
Last Update: April 10, 1997