title: Agonist-antagonist activity of anti-estrogens in the human breast cancer cell line MCF-7: an hypothesis for the interaction with a site distinct from the estrogen binding site.
abstract: Non-steroidal anti-estrogens exhibit an extremely complex pharmacology because of their estrogenic and anti-estrogenic effects in different species. Recently, we have reported evidence for an immunochemical difference in the estrogen receptor (ER) when it is occupied with anti-estrogens as compared to estrogens (Martin et al., 1988). In this study, we have compared immunoreactivity of MCF-7 cell estrogen receptor when bound to anti-estrogen versus estrogen. We show that the occupation of ER with antiproliferative concentrations of various anti-estrogens leads to the appearance of additional antigenic determinants for the H222 monoclonal anti-estrogen receptor antibody. When performing ER immunoassay after sedimentation of estrogen receptors on sucrose gradients, we show that exposure of new epitopes induced by anti-estrogens can occur on a 4 s molecular form related to the 66 kDa monomeric estrogen receptor. Also, when ER are previously occupied by estradiol, the addition of low anti-estrogen concentrations, which are unable to displace estradiol from the estrogen receptor, leads to a significant increase of H222 epitopes. Our results led us to propose a molecular model for anti-estrogen-receptor interaction in which their dual agonist/antagonist activity may be due to the occupation of distinct binding sites on the estrogen receptor.
authors.affiliation: Laboratoire de Cancérologie Expérimentale, Faculté de Médecine Secteur Nord, Marseille, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Berthois
authors.forename: M
authors.initials: M
authors.lastname: Pons
authors.forename: C
authors.initials: C
authors.lastname: Dussert
authors.forename: A
authors.initials: A
authors.lastname: Crastes de Paulet
authors.forename: P M
authors.initials: PM
authors.lastname: Martin
mesh_terms: D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002458:Cell Fractionation; D002499:Centrifugation, Density Gradient; D003600:Cytosol / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D011759:Pyrrolidines / Q000378:metabolism / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000378:metabolism*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D013876:Thiophenes / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D004965:Estrogen Antagonists; D011759:Pyrrolidines; D011960:Receptors, Estrogen; D013876:Thiophenes; D013629:Tamoxifen; C016601:afimoxifene; D004958:Estradiol; C025430:LY 117018