Peroxisome proliferator-activated receptor γ activation inhibits progesterone-stimulated human MUC1 expression

Mucin 1 (MUC1) is a type I transmembrane glycoprotein abundantly expressed on nearly all epithelial tissues and overexpressed by many cancer cells. Previous studies from our lab showed that progesterone receptor (PR)B is a strong stimulator of MUC1 gene expression. It is reported that liganded peroxisome proliferator-activated receptor γ(PPARγ) stimulates Muc1 expression in murine trophoblast. Here, we demonstrate that although the PPARγ ligand, rosiglitazone, stimulates the murine Muc1 promoter in HEC1A, a human uterine epithelial cell line, rosiglitazone alone, has no significant effect on basal human MUC1 promoter activity. In fact, rosiglitazone treatment antagonizes progesterone-stimulated human MUC1 promoter activity and protein expression in two human uterine epithelial cell lines and T47D human breast cancer cells. This response is antagonized by the PPARγ antagonist, GW9662, as well as a dominant-negative form of PPARγ, demonstrating the response is mediated by PPARγ. Additional studies indicate that PPARγ activation does not change PR binding to the MUC1 promoter but generally antagonizes progesterone activity by stimulating PRB degradation and inhibiting progesterone-induced PRB phosphorylation. Collectively, these studies indicate that PPARγ activation inhibits PRB activity through both acute (phosphorylation) and long-term (PRB degradation) pathways.