Mucin short variant S1

Mucin short variant S1, also called polymorphic epithelial mucin (PEM) or epithelial membrane antigen (EMA), is a mucin encoded by the MUC1 gene in humans.^[3] Mucin short variant S1 is a glycoprotein with extensive O-linked glycosylation of its extracellular domain. Mucins line the apical surface of epithelial cells in the lungs, stomach, intestines, eyes and several other organs.^[4] Mucins protect the body from infection by pathogen binding to oligosaccharides in the extracellular domain, preventing the pathogen from reaching the cell surface.^[5] Overexpression of MUC1 is often associated with colon, breast, ovarian, lung and pancreatic cancers.^[6] Joyce Taylor-Papadimitriou identified and characterised the antigen during her work with breast and ovarian tumors.

Structure

MUC1 is a member of the mucin family and encodes a membrane bound, glycosylated phosphoprotein. MUC1 has a core protein mass of 120-225 kDa which increases to 250-500 kDa with glycosylation. It extends 200-500 nm beyond the surface of the cell.^[7]

The protein is anchored to the apical surface of many epithelia by a transmembrane domain. Beyond the transmembrane domain is a SEA domain that contains a cleavage site for release of the large extracellular domain. The release of mucins is performed by sheddases.^[8] The extracellular domain includes a 20 amino acid variable number tandem repeat (VNTR) domain, with the number of repeats varying from 20 to 120 in different individuals. These repeats are rich in serine, threonine and proline residues which permits heavy o-glycosylation.^[7]

Multiple alternatively spliced transcript variants that encode different isoforms of this gene have been reported, but the full-length nature of only some has been determined.^[9]

MUC1 is cleaved in the endoplasmic reticulum into two pieces, the cytoplasmic tail including the transmembrane domain and the extracellular domain. These domains tightly associate in a non-covalent fashion.^[10] This tight, non-covalent association is not broken by treatment with urea, low pH, high salt or boiling. Treatment with sodium dodecyl sulfate triggers dissociation of the subunits.^[11] The cytoplasmic tail of MUC1 is 72 amino acids long and contains several phosphorylation sites.^[12]

Function

The protein serves a protective function by binding to pathogens^[13] and also functions in a cell signaling capacity.^[12]

Overexpression, aberrant intracellular localization, and changes in

• CTNND1,^[16]
• ERBB2,^[17][18]
• GRB2,^[19]
• JUP,^[17] and
• SOS1.^[18][19]

Role in cancer

The ability of chemotherapeutic drugs to access the cancer cells is inhibited by the heavy glycosylation in the extracellular domain of MUC1. The glycosylation creates a highly hydrophilic region which prevents hydrophobic chemotherapeutic drugs from passing through. This prevents the drugs from reaching their targets which usually reside within the cell. Similarly, the glycosylation has been shown to bind to growth factors. This allows cancer cells which produce a large amount of MUC1 to concentrate growth factors near their receptors, increasing receptor activity and the growth of cancer cells. MUC1 also prevents the interaction of immune cells with receptors on the cancer cell surface through steric hindrance. This inhibits an anti-tumor immune response.^[4]

Preventing cell death

MUC1 cytoplasmic tail has been shown to bind to p53. This interaction is increased by genotoxic stress. MUC1 and p53 were found to be associated with the p53 response element of the p21 gene promoter. This results in activation of p21 which results in cell cycle arrest. Association of MUC1 with p53 in cancer results in inhibition of p53-mediated apoptosis and promotion of p53-mediated cell cycle arrest.^[20]

Overexpression of MUC1 in

CA 27.29 (aka BR 27.29) and CA 15-3 measure different epitopes of the same protein antigen product of the MUC1 gene seen in breast cancer. CA 27.29 has enhanced sensitivity and specificity compared to CA 15-3 and is elevated in 30% of patients with low-stage disease and 60 to 70% of patients with advanced-stage breast cancer.

CA 27.29 levels over 100 U/mL and CA 15-3 levels over 25 U/mL are rare in benign conditions and suggest malignancy.

Immunohistochemistry

Using

• It is a marker of various types of cancer (see below).[32]
• In micropapillary carcinoma of the breast and bladder, MUC1 stains the stroma-facing surface of cell clusters of micropapillary units.^[32]
• It can distinguish systemic
  anaplastic large cell lymphoma (MUC1 positive) from cutaneous anaplastic large cell lymphoma (usually MUC1 negative).^[32]
• Although other antibodies, such as cytokeratins, are more commonly used for the identification of metastatic carcinoma deposits, EMA can be used to distinguish mesothelioma, in which it is restricted to the cell membranes and associated micovilli, from adenocarcinoma, in which it is diffusely spread through the cytoplasm.^[33]

As a therapeutic drug target

Using MUC1, vaccines are being tested against a type of blood cancer called

Because MUC1 is overexpressed (and differently glycosylated) in many cancers it has been investigated as a drug target, e.g. for the MUC1 vaccine ONT-10, which has had a phase 1 clinical study.^[35]

See also

• Cluster of differentiation
• List of histologic stains that aid in diagnosis of cutaneous conditions
• Mucin-1

References