MUC1 and cancer

Abstract

The MUC1 membrane mucin was first identified as the molecule recognised by mouse monoclonal antibodies directed to epithelial cells, and the cancers which develop from them. Cloning the gene showed that the extracellular domain is made up of highly conserved repeats of 20 amino acids, the actual number varying between 25 and 100 depending on the allele. Each tandem repeat contains five potential glycosylation sites, and between doublets of threonines and serines lies an immunodominant region which contains the epitopes recognised by most of the mouse monoclonal antibodies. The O-glycans added to the mucin produced by the normal breast are core 2 based and can be complex, while the O-glycans added to the breast cancer mucin are mainly core 1 based. This means that some core protein epitopes in the tandem repeat which are masked in the normal mucin are exposed in the cancer associated mucin. Since novel carbohydrate epitopes are also carried on the breast cancer mucin, the molecule is antigenically distinct from the normal breast mucin. (Changes in glycosylation in other epithelial cancers have been observed but are not so well documented.) Immune responses to MUC1 have been seen in breast and ovarian cancer patients and clinical studies have been initiated to evaluate the use of antibodies to MUC1 and of immunogens based on MUC1 for immunotherapy of these patients. The role of the carbohydrates in the immune response and in other interactions with the effector cells of the immune system is of particular interest and is discussed.

Th2-dominated antitumor immunity induced by DNA immunization with the genes coding for a basal core peptide PDTRP and GM-CSF

“…Importantly, MUC-1 is overexpressed by many carcinomas, including the breast, lung, pancreas, prostate, stomach, colon and ovarian cancers. 34,35 This phenomenon makes PDTRP a potential target for the induction of the antitumor immunity. Many reports have demonstrated that MUC-1 could serve as a tumor antigen for cancer immunotherapy.…”

MUC1 expression in human prostate cancer cell lines and primary tumors

“…Sections were rehydrated in a graded ethanol series (two 2 min washes each in 100, 95, 80, and 50% ethanol) at room temperature, followed by a 5 min flowing water rinse and a 20 min rinse in PBS. Rehydrated slides were quenched by two 10 min incubations in 50 mM NH 4 Cl in PBS, and blocked for 30 min at room temperature in normal donkey serum at a final dilution of 1 : 50 in PBS. Slides then were incubated with a mouse monoclonal 214D4 primary antibody (hybridoma medium diluted 1 : 1 in PBS) for 1 h at 371C.…”

“…Mucins are high molecular weight glycoproteins that are found almost exclusively on the apical surface of many glandular epithelia including the gastrointestinal, respiratory, urinary, and reproductive tracts (reviewed in Gendler, 1 Gendler and Spicer, 2 Lagow et al, 3 TaylorPapadimitriou et al 4 ). MUC1 is a type I transmembrane glycoprotein, consisting of a very large (1000-2200 amino acids) extracellular domain comprised of a series of 20-25 amino-acid tandem repeats, a 31-amino-acid transmembrane domain, and a short (72 amino acids) cytoplasmic tail.…”

“…Aside from its normal physiological roles, MUC1 also has been implicated in progression of numerous types of cancer including breast, colon, lung, gastric, and pancreatic cancers (reviewed in Gendler and Spicer, 2 TaylorPapadimitriou et al, 4 Ho et al 8 ). MUC1 expression in tumors is greatly increased and accompanied by altered glycosylation and aberrant expression patterns that become more diffuse when compared to the normal apically restricted pattern.…”

Transfected human dendritic cells to induce antitumor immunity

“…34 Several experimental models and clinical trials have proposed the use of different MUC1 antigen formulations. 35,36 We used the episomal vector pMRS 169 (kindly provided by Menarini Ricerche), containing a partial MUC1 cDNA coding for one tandem repeat deleted from the leader sequence, thus preventing membrane expression.…”