INTERFERENCE BETWEEN PROGESTERONE AND DIOXIN SIGNAL-TRANSDUCTION PATHWAYS - DIFFERENT MECHANISMS ARE INVOLVED IN REPRESSION BY THE PROGESTERONE-RECEPTOR A-ISOFORM AND B-ISOFORM

Interactions between transcription factors are an important means of r egulating gene transcription, leading to modifications in the pattern of gene expression and cell fate. In this study, we report that the pr ogesterone receptor (PR) can strongly interfere with transactivation m ediated by the arylhydrocarbon receptor (AhR) in T47D breast cancer ce lls. This interference was not only demonstrated by induction of a tra nsfected dioxin-responsive reporter plasmid but also on the AhR-mediat ed up-regulation of the endogenous cytochrome P450-1A1 activity. The i nterference was not mutual, as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TC DD), the most potent activator of the AhR, did not inhibit progestin-i nduced promoter activity. When the isoforms of the human PR, hPR-A and hPR-B, were expressed separately in HepG-2 hepatocarcinoma cells, bot h negatively interfered with the AhR signaling, indicating that the ef fect is not restricted to T47D cells. In addition, results obtained fr om studies with both antiprogestins and mutant receptors indicate diff erences in the underlying molecular mechanisms of repression for both PR isoforms, The suppression by hPR-A does not require additional gene expression or a full transcriptional competent conformation of the re ceptor. For the repressive effects of hPR-B, however, additional gene expression seems to be involved, as only the agonist-bound, wild-type hPR-B could clearly repress the TCDD-induced response. In conclusion, these studies highlight different mechanisms of repression for the pro gesterone receptor isoforms on the AhR-mediated trans-activation and u nderscore the importance of interactions between transcription factors of different families in the regulation of gene transcription.