Human MUC1 Mucin: A Multifaceted Glycoprotein

Abstract

Human MUC1 mucin, a membrane-bound glycoprotein, is a major component of the ductal cell surface of normal glandular cells. MUC1 is overexpressed and aberrantly glycosylated in carcinoma cells. The role MUC1 plays in cancer progression represents two sides of one coin: on the one hand, loss of polarity and overexpression of MUC1 in cancer cells interferes with cell adhesion and shields the tumor cell from immune recognition by the cellular arm of the immune system, thus favoring metastases; on the other hand, MUC1, in essence a self-antigen, is displaced and altered in malignancy and induces immune responses. Tumor-associated MUC1 has short carbohydrate sidechains and exposed epitopes on its peptide core; it gains access to the circulation and comes into contact with the immune system provoking humoral and cellular immune responses. Natural antibodies to MUC1 present in the circulation of cancer patients may be beneficial to the patient by restricting tumor growth and dissemination: early stage breast cancer patients with a humoral response to MUC1 have a better disease-specific survival. Several MUC1 peptide vaccines, differing in vectors, carrier proteins and adjuvants, have been tested in phase I clinical trials. They are capable of inducing predominantly humoral responses to the antigen, but evidence that these immune responses may be effective against the tumor in humans is still scarce.

MUC1/X Protein Immunization Enhances cDNA Immunization in Generating Anti-MUC1 α/β Junction Antibodies that Target Malignant Cells

“…Furthermore, formation and deposition of MUC1-anti-MUC1 circulating immune complexes can result in severe end-organ damage. These shortcomings likely contributed to the limited success of antitandem repeat MUC1 antibodies in clinical trials to date (28,(33)(34)(35)(36).…”

“…Tumor-associated MUC1 has been extensively studied as a tumor marker and as a target in cancer therapeutics (28)(29)(30)(31)(32)(33). In an attempt to target MUC1, a variety of anti-MUC1 antibodies have been generated, almost all of which react with epitopes contained within the highly immunogenic tandem 20-amino acid repeat sequence of the MUC1 a chain.…”

Regulation of Airway Mucin Gene Expression

“…It is expressed in secretory epithelial cells of the airways, GI tract, and female reproductive tract and is associated with goblet cells (124). Its function is not well defined yet, but it appears to play a role in antiadhesion of tumor cells or bacteria (124,125). It can mediate signal transduction responses through Ras, β-catenin, and p53.…”

Regulatory considerations for clinical development of cancer vaccines

“…An interesting example of this is the membrane-bound glycoprotein MUC1 mucin, which is expressed widely on the epithelial surface of glandular cells. 12 An abnormally glycosylated form of MUC1 is expressed on cells during inflammation, on pre-malignant lesions and on carcinoma cells. 13 Furthermore it has been shown that the presence of antibodies to the abnormal MUC1 following mumps infection is associated with a reduced incidence of ovarian cancer.…”