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

Area of Science:

• Reproductive Biology
• Molecular Endocrinology
• Epithelial Cell Biology

Background:

• MUC1 expression is regulated by progesterone (P) in the uterine epithelium.
• Two progesterone receptor (PR) isoforms, PRA and PRB, mediate P's effects.
• Species-specific differences in MUC1 response to P have been observed.

Purpose of the Study:

• To investigate the roles of PRA and PRB in regulating MUC1 gene activity in human uterine epithelial cells.
• To identify the DNA elements involved in progesterone-mediated MUC1 regulation.
• To compare the effects of P on MUC1 expression in mouse and human uterine tissues.

Main Methods:

• Transient transfection assays in HEC-1A human uterine epithelial cells.
• Site-directed mutagenesis of the MUC1 promoter region (-523 to -570 bp).
• Electrophoretic mobility shift assays (EMSA) to assess protein-DNA binding.
• In vivo studies using ovariectomized wild-type, PRKO, PRAKO, and PRBKO mice.

Main Results:

• Liganded PRB stimulated MUC1 gene activity in HEC-1A cells.
• PRA alone had minimal effect but antagonized PRB-mediated MUC1 stimulation.
• A region between -523 and -570 bp of the MUC1 promoter was critical for P response.
• Mutations in PRE half-sites within this region affected PRB-mediated stimulation and PR binding.
• In vivo, PRA mediated P antagonism of estrogen-stimulated MUC1 expression in mice.

Conclusions:

• Liganded PRB stimulates MUC1 expression in human uterine epithelial cells.
• Liganded PRA antagonizes MUC1 expression in both human and mouse uterine cells.
• Differential expression of PR isoforms likely contributes to species-specific MUC1 responses to progesterone.