MUC1-C oncoprotein as a target in breast cancer: activation of signaling pathways and therapeutic approaches

• Published in: Oncogene Vol. 32; no. 9; pp. 1073 - 1081
• Main Author: Kufe, D W
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.02.2013; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; 631/154/555; 631/67/1347; 631/80/86; AKT protein; Apoptosis; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - therapy; Care and treatment; catenin; Cell Biology; Cell death; Cell Line, Tumor; Cell Membrane - metabolism; Cell membranes; Drug therapy; Epidermal growth factor; Epidermal growth factor receptors; ErbB-2 protein; Extracellular signal-regulated kinase; Female; Genetic aspects; Human Genetics; Humans; Internal Medicine; Kinases; MAP kinase; Medicine; Medicine & Public Health; Metabolic pathways; Molecular Targeted Therapy; Mucin; Mucin-1 - metabolism; Nuclei; Oncogene Proteins - antagonists & inhibitors; Oncology; Oncoproteins; Physiological aspects; Protein kinase; Protein Subunits - metabolism; Protein-tyrosine kinase receptors; Proteins; RelA protein; review; Risk factors; Signal Transduction; Signaling; Transcription; Tumor proteins; Tyrosine; Wnt protein; Xenografts; β-Catenin; United States; breast cancer; targeted agents; MUC1; signaling pathways; oncoprotein
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2012.158

Mucin 1 (MUC1) is a heterodimeric protein formed by two subunits that is aberrantly overexpressed in human breast cancer and other cancers. Historically, much of the early work on MUC1 focused on the shed mucin subunit. However, more recent studies have been directed at the transmembrane MUC1-C-terminal subunit (MUC1-C) that functions as an oncoprotein. MUC1-C interacts with EGFR (epidermal growth factor receptor), ErbB2 and other receptor tyrosine kinases at the cell membrane and contributes to activation of the PI3K→AKT and mitogen-activated protein kinase kinase (MEK)→extracellular signal-regulated kinase (ERK) pathways. MUC1-C also localizes to the nucleus where it activates the Wnt/β-catenin, signal transducer and activator of transcription (STAT) and NF (nuclear factor)-κB RelA pathways. These findings and the demonstration that MUC1-C is a druggable target have provided the experimental basis for designing agents that block MUC1-C function. Notably, inhibitors of the MUC1-C subunit have been developed that directly block its oncogenic function and induce death of breast cancer cells in vitro and in xenograft models. On the basis of these findings, a first-in-class MUC1-C inhibitor has entered phase I evaluation as a potential agent for the treatment of patients with breast cancers who express this oncoprotein.