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 a ntiestrogen receptor Ig (IgGs) display estrogenic activity in MCF-7 ma mmary carcinoma cells. In this study, we investigated IgGs' mechanism of action. We showed that: 1) IgGs Fab fragments (which contain only o ne 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 MC F-7 cell surface labeling with fluorescent estradiol (E-2)-BSA conjuga tes; 3) this inhibition of E-2-BSA binding to membrane estrogen bindin g sites was largely caused by natural anti-E-2-BSA antibodies (Ab) sel ectively associated with the natural anti-ER Ab within IgGs; 4) furthe rmore, these natural anti-E-2-BSA Ab accounted for most of IgGs estrog enic activity in cell culture; 5) however, when incubated with cytosol ic ER, they did not behave like estrogens, but they decreased ER hormo ne binding capacity; and 6) although IgGs stimulated cAMP production, their anti-E-2-BSA Ab subpopulation did not. In conclusion, the estrog enic activity of IgGs does not involve Ab mimicking E-2 molecular conf iguration or ligand-independent cAMP mediated pathways, membrane Fc re ceptors, and membrane receptor cross-linking mechanisms. On the contra ry, IgGs seem to function by neutralizing estrogen-like epitopes, asso ciated with ER-related peptides, which might inhibit ER activation.