Natural antiestrogen receptor autoantibodies in man with estrogenic activity in mammary carcinoma cell culture: study of their mechanism of action; evidence for involvement of estrogen-like epitopes.
We previously reported that human natural autoantibodies enriched in antiestrogen receptor Ig (IgGs) display estrogenic activity in MCF-7 mammary carcinoma cells. In this study, we investigated IgGs' mechanism of action. We showed that: 1) IgGs Fab fragments (which contain only one antigen binding site) induced an estrogenic response in MCF-7 cells, producing estrogen receptor (ER) down-regulation and an increase in progesterone receptor concentration; 2) IgGs specifically inhibited MCF-7 cell surface labeling with fluorescent estradiol (E2)-BSA conjugates; 3) this inhibition of E2-BSA binding to membrane estrogen binding sites was largely caused by natural anti-E2-BSA antibodies (Ab) selectively associated with the natural anti-ER Ab within IgGs; 4) furthermore, these natural anti-E2-BSA Ab accounted for most of IgGs estrogenic activity in cell culture; 5) however, when incubated with cytosolic ER, they did not behave like estrogens, but they decreased ER hormone binding capacity; and 6) although IgGs stimulated cAMP production, their anti-E2-BSA Ab subpopulation did not. In conclusion, the estrogenic activity of IgGs does not involve Ab mimicking E2 molecular configuration or ligand-independent cAMP mediated pathways, membrane Fc receptors, and membrane receptor cross-linking mechanisms. On the contrary, IgGs seem to function by neutralizing estrogen-like epitopes, associated with ER-related peptides, which might inhibit ER activation.
Tassignon
J
J
Service de Médecine, Laboratoire d'Investigation Clinique H. J. Tagnon, Institut Jules Bordet, Brussels, Belgium.
Haeseleer
F
F
Borkowski
A
A
D000818:Animals; D001323:Autoantibodies / Q000494:pharmacology*; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D000242:Cyclic AMP / Q000096:biosynthesis; D000939:Epitopes / Q000276:immunology; D004967:Estrogens / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D016650:Fluorescein-5-isothiocyanate; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D007074:Immunoglobulin G / Q000494:pharmacology; D015674:Mammary Neoplasms, Animal / Q000378:metabolism / Q000473:pathology*; D011960:Receptors, Estrogen / Q000276:immunology* / Q000378:metabolism; D012710:Serum Albumin, Bovine; D014407:Tumor Cells, Cultured / Q000187:drug effects
D001323:Autoantibodies; D000939:Epitopes; D004967:Estrogens; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D011960:Receptors, Estrogen; D012710:Serum Albumin, Bovine; D000242:Cyclic AMP; D016650:Fluorescein-5-isothiocyanate