Neoplastic transformation of cultured mammalian cells by estrogens and estrogenlike chemicals.
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. 17beta-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.
Tsutsui
T
T
Department of Pharmacology, School of Dentistry at Tokyo, The Nippon Dental University, Japan.
Barrett
J C
JC
D000782:Aneuploidy; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D018736:DNA Adducts / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D004054:Diethylstilbestrol / Q000633:toxicity; D004622:Embryo, Mammalian; D004958:Estradiol / Q000633:toxicity; D004967:Estrogens / Q000633:toxicity*; D004968:Estrogens, Non-Steroidal / Q000633:toxicity; D005260:Female; D006801:Humans; D008647:Mesocricetus; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects; D009153:Mutagens / Q000633:toxicity
D018736:DNA Adducts; D004967:Estrogens; D004968:Estrogens, Non-Steroidal; D009153:Mutagens; D004958:Estradiol; D004054:Diethylstilbestrol