Gene: maps to 1q21-q24. Multiple
ER half-sites have been found in the promoter (Abe M. and Kufe D., 1993)
mRNA: size: polymorphic.
Protein: at least three MUC-1 gene products exist (data from Baruch A. et al., 1999):
- MUC1/REP is a polymorphic, type I transmembrane protein containing: 1) a large extracellular domain, primarily consisting of a 20-amino acid (aa) repeat motif (a region known as Variable Number (30 - 100) of Tandem Repeats - VNTR); 2) a transmembrane domain; 3) a 72-aa cytoplasmic tail. During its biosynthesis, the MUC1/REP protein is modified to a large extent, and a considerable number of O-linked sugar moieties confer mucin-like characteristics on the mature protein. Soon after translation, the MUC1/REP protein is cleaved; the two resulting products form a tight heterodimer complex composed of a large extracellular domain, linked by noncovalent, SDS-sensitive bonds to the much smaller protein molecule, which includes the cytoplasmic and transmembrane domains. The extracellular domain can be shed from the cell.
- MUC1/SEC is secreted by the cells. It has an extracellular domain that is identical to that present in MUC1/REP, but is devoid of a hydrophobic region that can anchor the protein to the cell membrane.
- MUC1/Y contains the cytoplasmic and transmembrane domains observed in MUC1/REP and MUC1/SEC, but its extracellular domain is smaller, lacking the repeat motif and its flanking region. MUC1/Y may undergo tyrosine and serine phosphorylation and can potentially bind second messenger proteins, such as GRB2, thereby initiating a signalling cascade (Zrihan-Licht S. et al., 1995).
- MUC-1 may act as a receptor. Its binding proteins are derived from the MUC1 gene and represent the secreted mucin-like polymorphic MUC1 proteins MUC1/SEC and MUC1/REP. The interaction between MUC1/SEC and MUC1/Y induces MUC1/Y phosphorylation and a modification of the cell shape (Baruch A. et al., 1999). It has been shown that ß-catenin interacts with the cytoplasmic domain of MUC1 (Yamamoto M. et al., 1997).
- MUC-1 is aberrantly expressed in breast cancers (Gendler S.J. et al, 1990).
- Studies on the relationship between MUC1 expression in breast cancer (cells) and (a) survival; (b)
ER status; have provided controversial results. This is probably explained by the diversity of anti-MUC1 antibodies used in these works. A number of antibodies exist (Karsten U. et al., 1998), and their differences in reactivity could be due to the fact that they have been raised against the VNTR region (see above) of MUC1 molecules exhibiting different degrees of glycosylation and "maturity" (McGuckin M.A. et al., 1995).
- Cancer-associated MUC1 seems able to reduce T-cell proliferation, an effect reversible by IL-2 (Agrawal B. et al., 1998).
- MUC-1 was found non-suitable for RT-PCR detection of submicroscopic lymph node metastases in breast cancer, as its transcript was also detected in the great majority of control (from non-cancer patients) lymph nodes tested (Merrie AEH et al., 1999).
Cell lines:
- The MA11 breast cancer cell (BCC) line, isolated from bone-marrow using an anti-MUC-1 antibody (BM-2), leads to brain metastases in 87% of nude mice injected in the left ventricle of the heart (Rye P.D. et al., 1996).
- 32 primary breast tumors were examined, by Southern blot DNA and northern blot RNA analyses, for allelic dosage and expression of the MUC1 gene. A correlation was found between acquisition of additional copies of MUC1 gene and high mRNA levels (p < 0.0001). These results identify a genetic mechanism responsible for MUC1 gene overexpression and support the hypothesis that a gene dosage effect of the long arm of chromosome 1 may be involved in the pathogenesis of breast cancer (Bièche I. and Lidereau R., 1997).
- MUC1 protein and mRNA have been found in the
ER-positive MCF-7 and BT-474 as well as in the
ER-negative MDA-MB-231 and SK-BR-3 BCC. Transcript level was higher in
ER+ than in
ER- cell lines. MUC1 levels were unrelated to confluence state of the cells and were not modulated by 17ß-estradiol or progesterone (De Bolòs et al., 1998).
- A decreased expression of MUC1 was found to induce
E-cadherin-mediated adhesion of the YMB-S and ZR-75-1S BCC normally proliferating in suspension culture without aggregation (Kondo K. et al., 1998). In YMB-S BCC, the anticancer agent adriamycin was able to induce
E-cadherin-mediated cell-cell adhesion by increasing expression of
E-cadherin and
beta-catenin and decreasing expression of MUC1 during breast cancer cell apoptosis induced by this drug (Yang S. et al., 1999).
- MUC1 was shown to react with intracellular adhesion molecule-1 (ICAM-1). At least six tandem repeats are needed (Regimbald L.H. et al., 1996; Kam J.L. et al., 1998).
- The tandem repeat peptide of MUC1 from T-47D BCC was found to be highly O-glycosylated (4.8 glycosylated sites per repeat, which compares to 2.6 sites per repeat for the mucin from milk). In addition to a modification by glycosylation, the MUC1 from T-47D BCC is altered by amino acid replacements (Muller S. et al., 1999).
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