Progesterone receptor isoforms A and B differentially regulate MUC1 expression in uterine epithelial cells.

MUC1 expression responds differently to changes in progesterone (P) levels in mouse vs. human uterine epithelium. Two isoforms of progesterone receptor, PRA and PRB, mediate the physiological effects of P. Using transient transfection of a human uterine epithelial cell line, HEC-1A, we showed that liganded PRB stimulated MUC1 gene activity. PRA alone had little effect on MUC1 promoter activity, but antagonized the PRB-mediated stimulation. The region from 523 to 570 bp upstream of the transcriptional start site was shown to be required for the P response. Mutation of two potential P-responsive element (PRE) half-sites in this region partially inhibited the PRB-mediated response, and one PRE half-site disrupted binding of both PRB and PRA to a consensus PRE in an EMSA. These along with other studies indicated that multiple cis elements in the -523- to -570-bp region cooperate to mediate P responsiveness, and that PR interaction with other transcription factors in this region is likely. Using ovariectomized wild-type, PR knockout (PRKO), PRAKO, and PRBKO mice, P antagonism of estrogen-stimulated Muc1 protein and mRNA expression was shown to be dependent on PRA. In summary, these data show that liganded PRB stimulates MUC1 expression in human uterine epithelial cells, whereas liganded PRA antagonizes MUC1 expression in both human and mouse uterine epithelial cells. The differential MUC1 response to P in these two species may be due to dissimilar expression of the two PR isoforms in the uterine epithelium.