title: Modulation of estrogen receptor-dependent reporter construct activation and G0/G1-S-phase transition by polycyclic aromatic hydrocarbons in human breast carcinoma MCF-7 cells.
abstract: It has been suggested that the estrogenicity of PAHs could contribute to their carcinogenic effects via increased tissue-specific cell proliferation. Both benzo[a]pyrene (BaP) and benz[a]anthracene (BaA) are known to weakly activate estrogen receptor (ER)-dependent reporter constructs. In this study, several other PAHs, including fluorene, fluoranthene, pyrene, chrysene, phenanthrene and anthracene, were found to act as very weak inducers of ER-mediated activity in the MCF-7 cell line stably transfected with a luciferase reporter gene. The effects of PAHs were time-dependent and they were not completely inhibited by antiestrogen ICI 182,780. In addition, BaP and BaA, as well as weakly estrogenic fluoranthene, significantly potentiated the maximum ER-mediated activity of 17beta-estradiol. Therefore, the effects of inhibitors of several types of protein kinases known to activate ERalpha in a ligand-independent manner were investigated. However, neither inhibitors nor inducers of extracellular signal-regulated kinases 1 and 2 (ERK1/2), phosphatidylinositol-3 kinase, protein kinase C, c-Src, or protein kinase A modified ER-mediated activity in this model. Neither estradiol nor BaA activated ERK1/2, two kinases suggested to play significant roles in ER signaling, suggesting that another kinase is involved in the observed phosphorylation of ERalpha. Similar to 17beta-estradiol, BaA stimulated G(0)/G(1)-S-phase transition in MCF-7 cells, which was fully suppressed by ICI 182,780. In conclusion, some PAHs can potentiate 17beta-estradiol-induced ER activation and stimulate cell cycle entry in vitro. However, their exact mode(s) of action and whether this phenomenon is of in vivo relevance remains to be elucidated.
authors.affiliation: Laboratory of Cytokinetics, Institute of Biophysics, Královopolská 135, 612 65 Brno, Czech Republic. hivrisek@ibp.cz
authors.forename: Jan
authors.initials: J
authors.lastname: Vondrácek
authors.forename: Alois
authors.initials: A
authors.lastname: Kozubík
authors.forename: Miroslav
authors.initials: M
authors.lastname: Machala
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects* / Q000235:genetics; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D016193:G1 Phase / Q000187:drug effects / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics*; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D011084:Polycyclic Aromatic Hydrocarbons / Q000378:metabolism / Q000633:toxicity*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D016192:Resting Phase, Cell Cycle / Q000187:drug effects / Q000235:genetics; D016196:S Phase / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D011084:Polycyclic Aromatic Hydrocarbons; D011960:Receptors, Estrogen