Mucin-1 subunit C (MUC1-C)

Mucin-1 subunit C (MUC1-C) is the transmembrane, oncogenic component of the Mucin-1 heterodimer, a protein that is aberrantly overexpressed and loses its apical polarity in the majority of human carcinomas [1, 2, 4]. Unlike the heavily glycosylated N-terminal subunit (MUC1-N) which is often shed into the circulation, MUC1-C remains anchored to the cell membrane where it functions as a critical integrator of inflammatory and proliferative signaling pathways [1, 4, 5]. The MUC1-C cytoplasmic domain is an intrinsically disordered scaffold that interacts with various effectors, including receptor tyrosine kinases (RTKs), PI3K, and β-catenin, to drive the epithelial-mesenchymal transition (EMT), cancer stemness, and epigenetic reprogramming [1, 3, 4, 16]. Furthermore, MUC1-C plays a significant role in immune evasion by inducing the expression of PD-L1 and suppressing anti-tumor immune responses [1, 4, 5, 16]. Therapeutic strategies targeting MUC1-C include peptide inhibitors that block its dimerization, monoclonal antibodies, antibody-drug conjugates (ADCs), and CAR-T cell therapies, many of which are currently in preclinical or early clinical development [1, 4, 9, 10].

Other names

MUC1-CMUC1 C-terminal subunitMucin-1 subunit betaCD227Epithelial membrane antigen (EMA)MAM6Polymorphic epithelial mucin (PEM)KL-6Breast carcinoma-associated antigen DF3EpisialinH23AG

MUC1-C targeted therapies work by several mechanisms: peptide inhibitors like GO-203 block the CQC-mediated dimerization of the cytoplasmic domain, preventing nuclear translocation and oncogenic signaling; monoclonal antibodies and ADCs target the extracellular domain to induce cell death or deliver cytotoxic agents; and CAR-T cells are engineered to recognize MUC1-C expressing cells and initiate direct lysis [1, 2, 4, 9, 10].