MUC1 is a transmembrane glycoprotein that modulates the interaction between the embryo and the uterine epithelial cell surface. MUC1 also is a tumor marker and has been implicated in the protection of cancer cells from immune cell attack, as well as in cell signaling in some tumors. We and others have shown that MUC1 expression is activated by progesterone (P), tumor necrosis factor- (TNF-), and interferon- (IFN-). Here we demonstrate that MUC1 expression is down-regulated by over-expression of members of the protein inhibitor of activated signal transducer and activator of transcription (PIAS) family, PIAS1, PIAS3, PIASx, PIASx, and PIASy, in human uterine epithelial cell lines, HES and HEC-1A, and in a breast cancer cell line, T47D. Treatments with P, TNF-, and IFN- were unable to overcome the repression by PIASy. PIASy repression of basal, P- and TNF--stimulated MUC1 promoter activity was not dependent on the PIASy sumoylation domain. In contrast, PIASy suppression of IFN- activated MUC1 promoter activity was dependent on the PIASy sumoylation domain. PIASy and progesterone receptor B (PRB) were localized to the nucleus upon P treatment, and siRNA knock-down of PIASy resulted in an increase in P-mediated stimulation of MUC1 protein expression. Over-expression of PIASy did not affect PRB binding to the MUC1 promoter, but surprisingly let to a loss of the corepressor, NCoR, which was recruited to the promoter in response to P. Collectively, these data indicate that PIASy may be a useful target for down-regulation of MUC1 expression in various contexts.