Mucins in cancer: function, prognosis and therapy

Abstract

Epithelial cells form a layer in which an apical surface is exposed to the external environment and to other forms of stress in ducts in specialized organs. As such, epithelial cells require robust defence mechanisms to avoid sustaining damage. Secreted mucins are highly glycosylated proteins that form a physical barrier, which protects epithelial cells from stress-induced damage. Transmembrane mucins also contribute to the physical barrier and transmit growth and survival signals to the interior of the cell. Deregulation of secreted mucin 2 (MUC2) production has provided an important link between inflammation and cancer. Expression of the transmembrane mucin MUC1 is upregulated in response to chronic inflammation. Aberrant overexpression of transmembrane mucins is associated with diverse human carcinomas and, somewhat paradoxically, certain haematological malignancies. Human cancers have exploited the function of these mucins in promoting growth and survival. Overexpression of transmembrane mucins contributes to oncogenesis by promoting receptor tyrosine kinase signalling, loss of epithelial cell polarity, constitutive activation of growth and survival pathways (for example, the Wnt–β-catenin and nuclear factor-κB pathways), and downregulation of stress-induced death pathways. Gene expression profiling and analysis of protein levels have demonstrated that overexpression of transmembrane mucins is associated with a poor prognosis in several different types of carcinomas. Circulating levels of the transmembrane mucins MUC1 and MUC16 are used to monitor the clinical course of patients with breast and ovarian cancer, respectively. Overexpression of the transmembrane mucins in human cancers has made them highly attractive targets for the development of vaccines, antibodies and drug inhibitors. Recent work has demonstrated that the MUC1 cytoplasmic domain is a direct drug target and that inhibition of MUC1 function blocks survival and tumorigenicity of human breast and prostate cancers in preclinical models.