Muc1 is a heavily [O-linked? O-glycosylated] transmembrane protein expressed on most secretory epithelium, including mammary gland and some hematopoietic cells. It is expressed abundantly in lactating mammary glands and overexpressed in >90% breast carcinomas and metastases. In normal mammary gland it is expressed in apical surface of glandular epithelium. In breast cancer Muc1 is overexpressed; is underglycosylated and the apical localization is lost. Muc1 is transcribed as a larger precursor which is cleaved to form a larger mucin like subunit (265-400kDa) and a smaller subunit (14-28kDa) noncovalently associated with each other. Transgenic Muc1 has been shown to associate with all four erbB receptors and localize with erbB1 (EGFR) in lactating glands1. Muc1 can act as a ligand for ICAM-1 on HUVEC cells; it can bind β-catenin, GSK3β and it associates with Grb2-SOS upon phosphorylation.
Protein structure and normal expression pattern of MUC1. Schematic diagram of the size and structure of the full-length MUC1 protein relative to the plasma membrane. The horizontal bar indicates the distance that most cell surface proteins extend into the pericellular space. The three major domains of MUC1 are indicated to the left: (1) an N-terminal, extracellular domain (ECTO); (2) a single, membrane spanning domain (TM); and (3) a C-terminal cytoplasmic domain (CT). A list of epithelial and non-epithelial human tissues that normally express MUC1 is indicated to the right. ()
The MUC1 mucin? is expressed on the luminal surface of most simple epithelial cells but in carcinomas, especially those of the breast and ovary, MUC1 is upregulated and aberrantly glycosylated. MUC1 contains a large amount of O-linked glycans which, in the mucin expressed by normal mammary epithelial cells, consist mainly of core 2 based structures carrying polylactosamine chains. However, the mucin expressed by breast carcinomas has shorter side-chains, often consisting of sialylated core 1 (Galbgr1–3GalNAc).in situ hybridization of primary breast tissue showed that a sialyltransferase (ST3Gal I), responsible for adding sialic acid to core 1 thereby terminating chain extension, is elevated in primary breast carcinomas when compared to normal or benign tissue. Furthermore, the level of mRNA expression encoding ST3Gal I is correlated to the intensity of staining seen with the antibody SM3, which specifically recognises underglycosylated, tumour associated MUC1. Thus, the aberrant glycosylation of MUC1 seen in breast carcinomas appears to be due, at least in part, to the elevation of ST3Gal I.()