ANTIESTROGENIC EFFECTS OF ALL-TRANS-RETINOIC ACID AND 1,25-DIHYDROXYVITAMIN D-3 IN BREAST-CANCER CELLS OCCUR AT THE ESTROGEN RESPONSE ELEMENT LEVEL BUT THROUGH DIFFERENT MOLECULAR MECHANISMS

Most breast tumors show estrogen-dependent growth and are thus suscept ible to antiestrogenic therapy. MCF-7 cells, obtained from a human est rogen dependent breast carcinoma, are widely used for studying the mod ulation of estrogenic responses by different effecters. All-trans-reti noic acid (RA) and 1,25-dihydroxyvitamin D-3 (Vit D-3) inhibited estro gen-induced growth of MCF-7 cells and their effect was potentiated by the classical antiestrogen, hydroxytamoxifen. In MCF-7 cells, we found that RA and Vit D-3 also inhibited estrogen-induced transcription; th is was shown both for an endogenous gene (pS2) and for various exogeno us transfected genes. Their inhibitory effect could not be reversed by increasing estradiol concentrations, showing that contrary to classic al antiestrogens, they did not compete with estradiol to bind the estr ogen receptor (ER). Analysis of the inhibitory mechanisms indicates th at RA and Vit D-3 receptors can directly or indirectly impair the bind ing of ER to the estrogen responsive element. The antagonist effect of RA would be found especially at DNA level since it seems to essential ly involve an estrogen responsive element. The antagonist effect of Vi t D-3 would be found especially at the ER level since it seems to conc ern estrogen binding and dimerization domains of ER. We conclude that the antiestrogenic effects of RA and Vit D-3 are similar since they ca n, via their receptors, interfere with estrogenic action at the estrog en responsive element level but that they are not identical since diff erent molecular mechanisms are involved.