Polynuclear aromatic hydrocarbon carcinogens as antiestrogens in MCF-7 human breast cancer cells: role of the Ah receptor.
Treatment of MCF-7 cells with 1.0 microM 3-methylcholanthrene (MC) caused a decrease in cell proliferation and [3H]thymidine uptake whereas no effects were observed at a lower (0.1 microM) concentration. Co-treatment of the cells with 1 nM 17 beta-estradiol plus 0.1 or 1.0 mu MC resulted in a significant inhibition of 17 beta-estradiol-induced growth and [3H]thymidine uptake. MC also inhibited the 17 beta-estradiol-induced secretion of the 52 kDa protein (procathepsin D) in MCF-7 cells and caused a concentration-dependent decrease in the nuclear estrogen receptor (ER) as determined by either velocity sedimentation analysis or immunoquantitation with human ER antibodies. The effects of several different polynuclear aromatic hydrocarbon (PAH) congeners on the nuclear ER in MCF-7 cells were also determined. Only those congeners which bound to the aryl hydrocarbon (Ah) receptor, namely benzo[a]pyrene, benz[a]anthracene, 7,12-dimethylbenz[a]anthracene and MC, caused a decrease in nuclear ER levels. In contrast, benzo[ghi]perylene, a congener which did not bind to the Ah receptor did not affect nuclear ER levels in MCF-7 cells. Moreover, with some congeners the decrease in nuclear ER levels could be observed without any significant induction of ethoxyresorufin O-deethylase activity, a P4501A1-dependent monooxygenase. These data suggest that the Ah receptor liganded with MC and related PAHs induced a broad spectrum of antiestrogenic responses in MCF-7 cells and complements the results of previous studies which report the antiestrogenic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and other halogenated aromatics which are also Ah receptor agonists.
Chaloupka
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K
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station 77843-4466.
Krishnan
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V
Safe
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D001943:Breast Neoplasms; D002273:Carcinogens / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004591:Electrophoresis, Polyacrylamide Gel; D004790:Enzyme Induction; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000633:toxicity*; D006801:Humans; D008748:Methylcholanthrene / Q000494:pharmacology; D010088:Oxidoreductases / Q000096:biosynthesis; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D011083:Polycyclic Compounds / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000187:drug effects / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured
D002273:Carcinogens; D004965:Estrogen Antagonists; D000072317:Polychlorinated Dibenzodioxins; D011083:Polycyclic Compounds; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; D011960:Receptors, Estrogen; D004958:Estradiol; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; D013936:Thymidine