Mucin 1, cell surface associated (MUC1) or polymorphic epithelial mucin (PEM) is a mucin encoded by the MUC1 gene in humans. MUC1 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. Mucins protect the body from infection by pathogen binding to oligosaccharides in the extracellular domain, preventing the pathogen from reaching the cell surface. Overexpression of MUC1 is often associated with colon, breast, ovarian, lung and pancreatic cancers. Joyce Taylor-Papadimitriou identified and characterised the antigen during her work with breast and ovarian tumors.
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.
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. 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.
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.
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. 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. The cytoplasmic tail of MUC1 is 72 amino acids long and contains several phosphorylation sites.
Overexpression, aberrant intracellular localization, and changes in glycosylation of this protein have been associated with carcinomas. e.g. The CanAg tumour antigen is a novel glycoform of MUC1. In the cell nucleus, the protein MUC1 regulates the activity of transcription factor complexes that have a documented role in tumor-induced changes of host immunity.
In histopathology, the product of the MUC-1 gene is commonly referred to as epithelial membrane antigen or EMA. Using immunohistochemistry, it can be identified in a wide range of secretory epithelia and their neoplastic equivalents. It can also be used for the identification of mesenchymal tumours, such as synovial sarcoma and ovarian granulosa cell tumours.
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.
MUC1 has been shown to interact with:
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.
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.
Overexpression of MUC1 in fibroblasts increased the phosphorylation of Akt. Phosphorylation of Akt results in phosphorylation of Bcl-2-associated death promoter. This results in dissociation of Bcl-2-associated death promoter with Bcl-2 and Bcl-xL. Activation was shown to be dependent on the upstream activation of PI3K. Additionally, MUC1 was shown to increase expression of Bcl-xL. Overexpression of MUC1 in cancer. The presence of free Bcl-2 and Bcl-xL prevents the release of cytochrome c from mitochondria, thereby preventing apoptosis. MUC1 cytoplasmic tail is shuttled to the mitochondria through interaction with hsp90. This interaction is induced through phosphorylation of the MUC1 cytoplasmic tail by Src (gene). Src is activated by the EGF receptor family ligand Neuregulin. The cytoplasmic tail is then inserted into the mitochondrial outer membrane. Localization of MUC1 to the mitochondria prevents the activation of apoptotic mechanisms.
Promoting tumor invasion
MUC1 cytoplasmic tail was shown to interact with Beta-catenin. A SXXXXXSSL motif was identified in MUC1 that is conserved with other beta-catenin binding partners. This interaction was shown to be dependent on cell adhesion. Studies have demonstrated that MUC1 is phosphorylated on a YEKV motif. Phosphorylation of this site has been demonstrated by LYN through mediation of interleukin 7, Src through mediation of EGFR, and PRKCD. This interaction is antagonized by degradation of beta-catenin by GSK3B. MUC1 blocks the phosphorylation-dependent degradation of beta-catenin by GSK3B. The end result is that increased expression of MUC1 in cancer increases stabilized beta-catenin. This promotes the expression of vimentin and CDH2. These proteins are associated with a mesenchymal phenotype, characterized by increased motility and invasiveness. In cancer cells, increased expression of MUC1 promotes cancer cell invasion through beta-catenin, resulting in the initiation of epithelial-mesenchymal transition which promotes the formation of metastases.
Cancer Antigens (CA) 27.29 and 15-3
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.
Diagnostic use in clinical pathology
- Epithelial marker
- breast micropapillary carcinoma
- bladder micropapillary carcinoma
- Distinguish systemic anaplastic large-cell lymphoma (MUC1+) from cutaneous anaplastic large-cell lymphoma (usually MUC1-)
Positive tumoral cells
- Adenocarcinomas (breast, colorectal, pancreatic, other)
- Carcinoid tumor
- Desmoplastic small round cell tumor (DSRCT)
- Epithelioid sarcoma
- Follicular dendritic cell sarcoma, interdigitating dendritic cell / reticulum cell sarcoma
- Lung: type II pneumocyte lesions (type II cell hyperplasia, dysplastic type II cells, apical alveolar hyperplasia)
- Anaplastic large-cell lymphoma, diffuse large B cell lymphoma (variable), plasmablastic lymphoma, primary effusion lymphoma
- Epithelioid mesotheliomas ()
- Myeloma, Plasmacytomas
- Renal cell carcinoma
- Synovial sarcoma (epithelial areas)
- Thymic carcinoma (often)
- Paget’s disease
Negative tumoral cells
- Adrenal cell carcinoma
- Hepatocellular carcinoma
- Germ cell tumors (except choriocarcinoma)
- Acquired cystic disease-associated renal cell carcinoma
- Leiomyosarcomas (usually)
- Solitary fibrous tumor (SFT)
- Myoepithelial cells
As a therapeutic drug target
Using MUC1, vaccines are being tested against a type of blood cancer called multiple myeloma. The technology could in theory be applied to 90 percent of all known cancers, including prostate and breast cancer, solid and non-solid tumors. This method would activate the immune system by training T-cells to search out and destroy cells that display a specific molecule (or marker) of MUC1. MUC1 is found on nearly all epithelial cells, but it is over expressed in cancer cells, and its associated glycans are shorter than those of non-tumor-associated MUC1.
- Cluster of differentiation
- List of histologic stains that aid in diagnosis of cutaneous conditions
- Gendler SJ, Lancaster CA, Taylor-Papadimitriou J, Duhig T, Peat N, Burchell J, Pemberton L, Lalani EN, Wilson D (September 1990). "Molecular cloning and expression of human tumor-associated polymorphic epithelial mucin". The Journal of Biological Chemistry. 265 (25): 15286–93. PMID 1697589.
- Hollingsworth MA, Swanson BJ (January 2004). "Mucins in cancer: protection and control of the cell surface". Nature Reviews Cancer. 4 (1): 45–60. doi:10.1038/nrc1251. PMID 14681689.
- Moncada DM, Kammanadiminiti SJ, Chadee K (July 2003). "Mucin and Toll-like receptors in host defense against intestinal parasites". Trends Parasitol. 19 (7): 305–311. doi:10.1016/S1471-4922(03)00122-3. PMID 12855381.
- Gendler SJ (July 2001). "MUC1, the renaissance molecule". J. Mammary Gland Biol Neoplasia. 6 (3): 339–353. doi:10.1023/A:1011379725811. PMID 11547902.
- Brayman M, Thathiah A, Carson DD (January 2004). "MUC1: a multifunctional cell surface component of reproductive tissue epithelia". Reprod Biol Endocrinol. 2: 4. doi:10.1186/1477-7827-2-4. PMC 320498. PMID 14711375.
- Hattrup CL, Gendler SJ (2008). "Structure and function of the cell surface (tethered) mucins". Annual Review of Physiology. 70: 431–57. doi:10.1146/annurev.physiol.70.113006.100659. PMID 17850209.
- "Entrez Gene: SEA Domain of MUC1".
- Ligtenberg MJ, Kruijshaar L, Buijs F, van Meijer M, Litvinov SV, Hilkens J (March 1992). "Cell-associated episialin is a complex containing two proteins derived from a common precursor". The Journal of Biological Chemistry. 267 (9): 6171–7. PMID 1556125.
- Julian J, Carson DD (May 2002). "Formation of MUC1 metabolic complex is conserved in tumor-derived and normal epithelial cells". Biochem Biophys Res Commun. 293 (4): 1183–1190. doi:10.1016/S0006-291X(02)00352-2. PMID 12054500.
- Singh PK, Hollingsworth MA (August 2006). "Cell surface-associated mucins in signal transduction". Trends Cell Biol. 16 (9): 467–476. doi:10.1016/j.tcb.2006.07.006. PMID 16904320.
- Lindén SK, Sheng YH, Every AL, Miles KM, Skoog EC, Florin TH, Sutton P, McGuckin MA (October 2009). "MUC1 limits Helicobacter pylori infection both by steric hindrance and by acting as a releasable decoy". PLOS Pathog. 5 (10): e1000617. doi:10.1371/journal.ppat.1000617. PMC 2752161. PMID 19816567.
- Tolcher AW, Ochoa L, Hammond LA, Patnaik A, Edwards T, Takimoto C, Smith L, de Bono J, Schwartz G, Mays T, Jonak ZL, Johnson R, DeWitte M, Martino H, Audette C, Maes K, Chari RV, Lambert JM, Rowinsky EK (January 2003). "Cantuzumab mertansine, a maytansinoid immunoconjugate directed to the CanAg antigen: a phase I, pharmacokinetic, and biologic correlative study". J. Clin. Oncol. 21 (2): 211–22. doi:10.1200/JCO.2003.05.137. PMID 12525512.
- Vlahopoulos, SA (15 August 2017). "Aberrant control of NF-κB in cancer permits transcriptional and phenotypic plasticity, to curtail dependence on host tissue: molecular mode". Cancer Biology & Medicine. 14 (3): 254–270. doi:10.20892/j.issn.2095-3941.2017.0029. PMC 5570602. PMID 28884042.
- Cooper K; Leong AS-Y; Leong JW-M (2003). Manual of diagnostic antibodies for immunohistology. London: Greenwich Medical Media. pp. 205–206. ISBN 978-1-84110-100-2.
- Li Y, Kufe D (February 2001). "The Human DF3/MUC1 carcinoma-associated antigen signals nuclear localization of the catenin p120(ctn)". Biochem. Biophys. Res. Commun. 281 (2): 440–3. doi:10.1006/bbrc.2001.4383. PMID 11181067.
- Li Y, Yu WH, Ren J, Chen W, Huang L, Kharbanda S, Loda M, Kufe D (August 2003). "Heregulin targets gamma-catenin to the nucleolus by a mechanism dependent on the DF3/MUC1 oncoprotein". Mol. Cancer Res. 1 (10): 765–75. PMID 12939402.
- Schroeder JA, Thompson MC, Gardner MM, Gendler SJ (April 2001). "Transgenic MUC1 interacts with epidermal growth factor receptor and correlates with mitogen-activated protein kinase activation in the mouse mammary gland". J. Biol. Chem. 276 (16): 13057–64. doi:10.1074/jbc.M011248200. PMID 11278868.
- Pandey P, Kharbanda S, Kufe D (September 1995). "Association of the DF3/MUC1 breast cancer antigen with Grb2 and the Sos/Ras exchange protein". Cancer Res. 55 (18): 4000–4003. PMID 7664271.
- Wei X, Xu H, Kufe D (February 2005). "Human MUC1 oncoprotein regulates p53-responsive gene transcription in the genotoxic stress response". Cancer Cell. 7 (2): 167–178. doi:10.1016/j.ccr.2005.01.008. PMID 15710329.
- Raina D, Kharbanda S, Kufe D (May 2004). "The MUC1 oncoprotein activates the anti-apoptotic phosphoinositide 3-kinase/Akt and Bcl-xL pathways in rat 3Y1 fibroblasts". J Biol Chem. 279 (20): 20607–20612. doi:10.1074/jbc.M310538200. PMID 14999001.
- Ren J, Bharti A, Raina D, Chen W, Ahmad R, Kufe D (January 2006). "MUC1 oncoprotein is targeted to mitochondria by heregulin-induced activation of c-Src and the molecular chaperone HSP90". Oncogene. 25 (1): 20–31. doi:10.1038/sj.onc.1209012. PMID 16158055.
- Yamamoto M, Bharti A, Li Y, Kufe D (May 1997). "Interaction of the DF3/MUC1 breast carcinoma-associated antigen and beta-catenin in cell adhesion". J. Biol. Chem. 272 (19): 12492–4. doi:10.1074/jbc.272.19.12492. PMID 9139698.
- Li Y, Chen W, Ren J, Yu WH, Li Q, Yoshida K, Kufe D (2003). "DF3/MUC1 signaling in multiple myeloma cells is regulated by interleukin-7". Cancer Biol. Ther. 2 (2): 187–93. doi:10.4161/cbt.2.2.282. PMID 12750561.
- Li Y, Kuwahara H, Ren J, Wen G, Kufe D (March 2001). "The c-Src tyrosine kinase regulates signaling of the human DF3/MUC1 carcinoma-associated antigen with GSK3 beta and beta-catenin". J. Biol. Chem. 276 (9): 6061–4. doi:10.1074/jbc.C000754200. PMID 11152665.
- Li Y, Ren J, Yu W, Li Q, Kuwahara H, Yin L, Carraway KL, Kufe D (September 2001). "The epidermal growth factor receptor regulates interaction of the human DF3/MUC1 carcinoma antigen with c-Src and beta-catenin". J. Biol. Chem. 276 (38): 35239–42. doi:10.1074/jbc.C100359200. PMID 11483589.
- Ren J, Li Y, Kufe D (May 2002). "Protein kinase C delta regulates function of the DF3/MUC1 carcinoma antigen in beta-catenin signaling". J. Biol. Chem. 277 (20): 17616–22. doi:10.1074/jbc.M200436200. PMID 11877440.
- Li Y, Bharti A, Chen D, Gong J, Kufe D (December 1998). "Interaction of glycogen synthase kinase 3beta with the DF3/MUC1 carcinoma-associated antigen and beta-catenin". Mol. Cell. Biol. 18 (12): 7216–24. doi:10.1128/mcb.18.12.7216. PMC 109303. PMID 9819408.
- Huang L, Chen D, Liu D, Yin L, Kharbanda S, Kufe D (November 2005). "MUC1 oncoprotein blocks glycogen synthase kinase 3beta-mediated phosphorylation and degradation of beta-catenin". Cancer Res. 65 (22): 10413–10422. doi:10.1158/0008-5472.CAN-05-2474. PMID 16288032.
- Schroeder JA, Adriance MC, Thompson MC, Camenisch TD, Gendler SJ (March 2003). "MUC1 alters beta-catenin-dependent tumor formation and promotes cellular invasion". Oncogene. 22 (9): 1324–32. doi:10.1038/sj.onc.1206291. PMID 12618757.
- Roy LD, Sahraei M, Subramani DB, Besmer D, Nath S, Tinder TL, Bajaj E, Shanmugam K, Lee YY, Hwang SI, Gendler SJ, Mukherjee P (March 2011). "MUC1 enhances invasiveness of pancreatic cancer cells by inducing epithelial to mesenchymal transition". Oncogene. 30 (12): 1449–1459. doi:10.1038/onc.2010.526. PMC 3063863. PMID 21102519.
- Gaidzik N, Westerlind U, Kunz H (May 2013). "The development of synthetic antitumour vaccines from mucin glycopeptide antigens". Chem Soc Rev. 42 (10): 4421–42. doi:10.1039/c3cs35470a. PMID 23440054.
- Nemunaitis J, Bedell C, Klucher K, Vo A, Whiting S (2013). "Phase 1 dose escalation of ONT-10, a therapeutic MUC1 vaccine, in patients with advanced cancer". Journal for ImmunoTherapy of Cancer. 1 (Suppl 1): P240. doi:10.1186/2051-1426-1-S1-P240. ISSN 2051-1426. PMC 3990302.
- Peterson JA, Scallan CD, Ceriani RL, Hamosh M (2002). "Structural and Functional Aspects of Three Major Glycoproteins of the Human Milk Fat Globule Membrane". Bioactive Components of Human Milk. Advances in Experimental Medicine and Biology. 501. pp. 179–87. doi:10.1007/978-1-4615-1371-1_23. ISBN 978-1-4613-5521-2. PMID 11787681.
- Hu XF, Yang E, Li J, Xing PX (2006). "MUC1 cytoplasmic tail: a potential therapeutic target for ovarian carcinoma". Expert Rev Anticancer Ther. 6 (8): 1261–71. doi:10.1586/14737126.96.36.1991. PMID 16925492.
- Leroy X, Buisine MP, Leteurtre E, et al. (2007). "[MUC1 (EMA): A key molecule of carcinogenesis?]". Annales de Pathologie. 26 (4): 257–66. doi:10.1016/S0242-6498(06)70718-0. PMID 17128152.
- Li Y, Cozzi PJ (2007). "MUC1 is a promising therapeutic target for prostate cancer therapy". Current Cancer Drug Targets. 7 (3): 259–71. doi:10.2174/156800907780618338. PMID 17504123.
- Mahanta S, Fessler SP, Park J, Bamdad C (April 2008). "A minimal fragment of MUC1 mediates growth of cancer cells". PLOS One. 3 (4): e2054. doi:10.1371/journal.pone.0002054. PMC 2329594. PMID 18446242.
- Hikita ST, Kosik KS, Clegg DO, Bamdad C (October 2008). "MUC1* mediates the growth of human pluripotent stem cells". PLOS One. 3 (10): e3312. doi:10.1371/journal.pone.0003312. PMC 2553196. PMID 18833326.
- Fessler SP, Wotkowicz MT, Mahanta S, Bamdad C (2009). "MUC1* is a determinant of trastuzumab (Herceptin) resistance in breast cancer cells". Breast Cancer Res Treat. 118 (1): 113–24. doi:10.1007/s10549-009-0412-3. PMID 19415485.
- Zhan XX, Zhao B, Diao C, Cao Y, Cheng RC (2015). "Expression of MUC1 and CD176 (Thomsen-Friedenreich antigen) in papillary thyroid carcinomas". Endocr. Pathol. 26 (1): 21&ndash, 6. doi:10.1007/s12022-015-9356-9. PMID 25614211.