Synergistic stimulation of MUC1 expression in normal breast epithelia and breast cancer cells by interferon‐γ and tumor necrosis factor‐α

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Abstract
The MUC1 gene encodes a transmembrane mucin glycoprotein that is overexpressed in human breast cancers. Persistent stimulation by proinflammatory cytokines may contribute to increased MUC1 transcription by tumor cells. We demonstrate that MUC1 expression in T47D breast cancer cells and normal human mammary epithelial cells (HMEC) is enhanced by tumor necrosis factor-α (TNF-α) in the presence of interferon-γ (IFN-γ). MUC1 responsiveness to these cytokines was modest in T47D cells and robustly induced in HMEC. Transient transfection of T47D cells with mutant MUC1 promoter constructs revealed that a κB site at −589/−580 and the STAT-binding element at −503/−495 and were required for cooperative stimulation by TNFα and IFN-γ. Binding of NFκB p65 to the MUC1 κB site was induced by TNF-α treatment, as demonstrated by electrophoretic mobility shift assay. Specific mutation of the κB site prevented binding of NFκB p65 and blocked TNF-α stimulation of MUC1 promoter activity. Collectively, these studies demonstrate synergistic stimulation of MUC1 expression by TNF-α and IFN-γ that is mediated by independent actions of NFκB p65 and STAT1α upon κB and STAT sites, respectively, in the MUC1 promoter. Strong induction of MUC1 expression by these proinflammatory cytokines is clearly evident in normal mammary epithelium. In contrast, breast tumor cells appear to override normal regulatory responses via as yet undefined cis-elements. J. Cell. Biochem. 86: 759–772, 2002.