The MUC1 heterodimeric protein is aberrantly overexpressed at high levels in most human carcinomas and certain hematologic malignancies. As documented above, of the ~1.6 million tumors diagnosed each year in the US, about 900,000 overexpress MUC1 in association with a poor prognosis. MUC1 has thus become a highly attractive target for the development of new anti-cancer agents, including vaccines, antibodies and small molecules. However, there are presently no approved agents that target MUC1, in part because there has been limited information about how MUC1 contributes to the malignant phenotype.
MUC1 is a Heterodimeric Complex
MUC1 is encoded by a single transcript and, following translation, undergoes auto-cleavage into two subunits that form a stable non-covalent complex. The extracellular MUC1 N-terminal subunit, designated MUC1-N, is the mucin component of the heterodimer with glycosylated variable numbers of tandem repeats (Fig. 1). MUC1-N associates with the cell surface through binding to the transmembrane MUC1 C-terminal subunit (MUC1-C) (Fig. 1).
Schematic representation of the MUC1 heterodimer at the surface of normal epithelial cells. In the response to stress, MUC1-N is shed from the cell surface and MUC1-C signals proliferation and survival signals to the interior of the cell. The MUC1-N and MUC1-C nomenclature is used to denote positioning of the subunits following cleavage from a single polypeptide.
Research on the MUC1-C receptor subunit has provided new insights into how MUC1-C induces transformation and is of importance to human cancers, and how to target MUC1-C as an approach for anticancer treatment.
MUC1-C is an Oncogenic Protein
MUC1-C consists of a 58 amino acid extracellular domain, a 28 amino acid transmembrane domain and a 72 amino acid cytoplasmic domain (Fig. 2A). The MUC1-C extracellular domain (ED) is glycosylated on Asn-36, which then functions as a galectin-3 ligand binding site. Galectin-3, in turn, functions as a bridge to physically associate MUC1-C with EGFR and other cell surface molecules. (Fig. 2B).
Structure of the oncogenic MUC1-C transmembrane subunit.
The MUC1-C cytoplasmic domain (CD) is an intrinsically disordered protein as found in other oncoproteins that have the plasticity to function as nodes by interacting with multiple signaling pathways. For instance, the MUC1-C cytoplasmic domain binds directly with β-catenin, stabilizes β-catenin, and thereby activates the canonical WNT signaling pathway (Fig. 3). These findings provided the first evidence that MUC1-C interacts with a signaling pathway that is associated with transformation and provided the basis for demonstrating that MUC1-C and, specifically, the MUC1-C cytoplasmic domain induces anchorage-independent growth and tumorigenicity. The MUC1-C cytoplasmic domain also activates the NF-kB and STAT1/3 pathways, and interacts with other transcription factors and multiple kinases linked to transformation. (Fig. 3).
Amino acid sequence of the MUC1-C cytoplasmic domain (CD). Highlighted are the kinases that phosphorylate the cytoplasmic domain and thereby regulate interactions with the indicated signaling pathways that promote repression of tumor suppressor genes (TSGs), epithelial-mesenchymal transition (EMT), immune evasion, proliferation and survival.
Notably, the MUC1-C cytoplasmic domain contains a CQC motif that is necessary and sufficient for formation of homodimers, localization to the nucleus and oncogenic function (Fig. 3). These findings have supported the premise that the MUC1-C CQC motif is a potential Achilles’ heel for targeting MUC1-C as a treatment for cancer.
MUC1-C is a Druggable Target
The aberrant overexpression of MUC1-C in diverse human malignancies, the interaction between the MUC1-C subunit and multiple effectors associated with transformation, and the demonstration that the MUC1-C cytoplasmic domain is sufficient to induce transformation have all supported the notion that MUC1-C is a highly attractive target for cancer treatment. In addition, the findings that MUC1-CD induces gene signatures that are predictive of poor outcomes for patients with breast and lung cancer have provided further support for the importance of MUC1-C as a therapeutic target. However and significantly, there are presently no approved agents against MUC1-C for the treatment of patients with cancer.