Inhibition of estrogen-induced progesterone receptor in MCF-7 human breast cancer cells by aryl hydrocarbon (Ah) receptor agonists.
17 beta-Estradiol (E2) induces progesterone receptor (PR) binding, immunoreactive protein, nuclear PR formation and PR mRNA levels in MCF-7 human breast cancer cells. Gel mobility shift analysis of nuclear extracts from E2-treated cells also exhibited a higher intensity retarded band associated with formation of a PR complex with a consensus [32P]progesterone/glucocorticoid responsive element. In contrast, 1 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alone did not alter or decrease these same responses in MCF-7 cells; however, in cells co-treated with 1 nM TCDD plus 1 nM E2, TCDD significantly inhibited all the E2-induced responses. Scatchard analysis of PR binding demonstrated that TCDD decreased the number of E2-induced PR cellular binding sites but not the binding affinity of the PR for a radiolabeled promegestrone. In parallel studies, 3-methylcholanthrene, a prototypical polynuclear aromatic hydrocarbon, also inhibited E2-induced PR binding and immunoreactive protein. For a series of halogenated aromatics including 2,3,7,8- and 1,2,7,8-tetrachlorodibenzofuran, 1,3,7,8-TCDD and 6-methyl-1,3,8-trichlorodibenzofuran, their rank order potency for inhibiting E2-induced PR binding paralleled their rank order binding to the aryl hydrocarbon (Ah) receptor. These results support a role for the Ah receptor in mediating the antiestrogenic activity of polynuclear and halogenated aromatic hydrocarbons and illustrate cross-talk between the Ah and estrogen receptor signal transduction pathways.
Harper
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Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station 77843-4466.
Wang
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Liu
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Safe
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D015152:Blotting, Northern; D001943:Breast Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006838:Hydrocarbons / Q000494:pharmacology; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000502:physiology; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors* / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
D004967:Estrogens; D006838:Hydrocarbons; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D011980:Receptors, Progesterone; D004958:Estradiol