RU486 EXERTS ANTIESTROGENIC ACTIVITIES THROUGH A NOVEL PROGESTERONE-RECEPTOR-A FORM-MEDIATED MECHANISM

The human progesterone receptor (hPR) exists in two distinct forms in most cells, hPR-A and hPR-B. Both receptor isoforms exhibit distinct b iological functions and demonstrate a cell- and promoter-specific abil ity to regulate gene transcription. Interestingly, in cell contexts wh ere PR-A is transcriptionally inactive, it acts as a progesterone-depe ndent inhibitor of estrogen receptor function. Coexpression of the hum an estrogen receptor with the A form (but not the B form) of the human progesterone receptor resulted in a ligand-dependent inhibition of es trogen receptor-mediated gene transcription. The antiprogestins RU486 (Mifepristone) and ZK98299 (Onapristone) and related antiprogestins we re ah effective ''noncompetitive'' inhibitors of the estrogen receptor in this assay as none of these compounds interacted directly with the estrogen receptor. This observation may explain in part the observed tissue-specific antiestrogenic effects of RU486 and further indicates that the antiestrogenic activities of antiprogestins may be intrinsic to their biological function. This important new information defines n ovel activities of progesterone receptor ligands and may alter the way in which we define progesterone receptor modulators for future clinic al applications. In addition, these data reveal that the A form of the progesterone receptor plays a key role in modulating estrogen recepto r function in cells where both receptors are expressed.