Nuclear factor-KB (NF-KB) is constitutively activated in diverse human malignancies. The mucin 1 (MUC1) oncoprotein is overexpressed in human carcinomas and, like NF-KB, blocks cell death and induces transformation. The present studies show that MUC1 constitutively associates with NF-KB p65 in carcinoma cells. The MUC1 COOH-terminal subunit (MUC1-C) cytoplasmic domain binds directly to NF-KB p65 and, importantly, blocks the interaction between NF-KB p65 and its inhibitor IKBA. We show that NF-KB p65 and MUC1-C constitutively occupy the promoter of the Bcl-xL gene in carcinoma cells and that MUC1-C contributes to NF-KBmediated transcriptional activation. Studies in nonmalignant epithelial cells show that MUC1-C interacts with NF-KB in the response to tumor necrosis factor-A stimulation. Moreover, tumor necrosis factor-A induces the recruitment of NF-KB p65-MUC1-C complexes to NF-KB target genes, including the promoter of the MUC1 gene itself. We also show that an inhibitor of MUC1-C oligomerization blocks the interaction with NF-KB p65 in vitro and in cells. The MUC1-C inhibitor decreases MUC1-C and NF-KB p65 promoter occupancy and expression of NF-KB target genes. These findings indicate that MUC1-C is a direct activator of NF-KB p65 and that an inhibitor of MUC1 function is effective in blocking activation of the NF-KB pathway. [Cancer Res 2009;69(17):7013-21]

The mucin 1 (MUC1) oncoprotein is aberrantly overexpressed by ∼90% of human breast cancers. However, there are no effective agents that directly inhibit MUC1 and induce death of breast cancer cells. We have synthesized a MUC1 inhibitor (called ) that binds to the MUC1 cytoplasmic domain and blocks the formation of MUC1 oligomers in cells. GO-201, and not an altered version, attenuates targeting of MUC1 to the nucleus of human breast cancer cells, disrupts redox balance, and activates the DNA damage response. GO-201 also arrests growth and induces necrotic death. By contrast, the MUC1 inhibitor has no effect on cells null for MUC1 expression or nonmalignant mammary epithelial cells. Administration of GO-201 to nude mice bearing human breast tumor xenografts was associated with loss of tumorigenicity and extensive necrosis, which results in prolonged regression of tumor growth. These findings show that targeting the MUC1 oncoprotein is effective in inducing death of human breast cancer cells in vitro and in tumor models. [Cancer Res 2009;69(12):5133-41]

The MUC1 heterodimeric transmembrane glycoprotein is aberrantly overexpressed by diverse human carcinomas. Galectin-3 is a beta-galactoside binding protein that has also been associated with the development of human cancers. The present results demonstrate that MUC1 induces galectin-3 expression by a posttranscriptional mechanism. We show that the MUC1 C-terminal subunit is glycosylated on Asn-36 and that this modification is necessary for upregulation of galectin-3. N-glycosylated MUC1-C increases galectin-3 mRNA levels by suppressing expression of the microRNA miR-322 and thereby stabilizing galectin-3 transcripts. The results show that, in turn, galectin-3 binds to MUC1-C at the glycosylated Asn-36 site. The significance of the MUC1-C-galectin-3 interaction is supported by the demonstration that galectin-3 forms a bridge between MUC1 and the epidermal growth factor receptor (EGFR) and that galectin-3 is essential for EGF-mediated interactions between MUC1 and EGFR. These findings indicate that MUC1 and galectin-3 function as part of a miR-322-dependent regulatory loop.