Review
MUC1: a multifaceted oncoprotein with a key role in cancer progression

https://doi.org/10.1016/j.molmed.2014.02.007Get rights and content

Highlights

  • MUC1 promotes growth, metastasis, and resistance to drugs in cancer.

  • In tumors, the cytoplasmic tail of MUC1 acts as an oncogenic signaling molecule.

  • MUC1 regulates gene expression at transcriptional and post-transcriptional levels.

  • MUC1 is critical for maintaining ‘stemness’ in embryonic and cancer stem cells.

The transmembrane glycoprotein Mucin 1 (MUC1) is aberrantly glycosylated and overexpressed in a variety of epithelial cancers, and plays a crucial role in progression of the disease. Tumor-associated MUC1 differs from the MUC1 expressed in normal cells with regard to its biochemical features, cellular distribution, and function. In cancer cells, MUC1 participates in intracellular signal transduction pathways and regulates the expression of its target genes at both the transcriptional and post-transcriptional levels. This review highlights the structural and functional differences that exist between normal and tumor-associated MUC1. We also discuss the recent advances made in the use of MUC1 as a biomarker and therapeutic target for cancer.

Section snippets

Mucin 1: a membrane tethered glycoprotein

Mucin 1 (MUC1; also known as episialin, PEM, H23Ag, EMA, CA15-3, and MCA) is a single pass type I transmembrane protein with a heavily glycosylated extracellular domain that extends up to 200–500 nm from the cell surface 1, 2. MUC1 (see Glossary) is normally expressed in the glandular or luminal epithelial cells of the mammary gland, esophagus, stomach, duodenum, pancreas, uterus, prostate, and lungs, and to a lesser extent, in hematopoietic cells 3, 4. It is absent in the skin epithelium and in

Structure of MUC1

The MUC1 gene encodes a single polypeptide chain which, due to conformational stress, is autoproteolytically cleaved immediately after translation at the GSVVV motif, located within the Sea urchin sperm protein enterokinase and agrin (SEA) domain, into two peptide fragments: the longer N-terminal subunit (MUC1-N) and the shorter C-terminal subunit (MUC1-C) (Figure 1A) 1, 10. Extracellularly, the two subunits remain associated through stable hydrogen bonds.

MUC1-N is composed of the proline,

Regulation of MUC1 gene expression

MUC1 is encoded by a gene located on the long arm (q) of chromosome 1 at position 21, a region frequently altered in breast cancer cells [25]. Overexpression of MUC1 in cancer is caused by increases in gene dosage and level of transcription, and by a loss of post-transcriptional regulation. Studies on epigenetic regulation have shown that methylation of histone H3-K9 and the CpG islands in the MUC1 promoter (close to the transcriptional start site; –174 to –182 bp) cause transcriptional

MUC1 isoforms

MUC1 contains seven exons, where exons 1–4 encode MUC1-N and exons 4–7 encode MUC1-C (Figure 2A). In humans, there are several isoforms of MUC1 that result from alternative splicing, exon skipping, and intron retention. A recent study identified 78 isoforms of MUC1 [30], with the most common isoforms being MUC1/A, MUC1/B, MUC1/C, MUC1/D, MUC1/X (or MUC1/Z), MUC1/Y, and MUC1/ZD. MUC1/A, MUC1/B, MUC1/C, and MUC1/D, encoding ‘full-length’ MUC1, arise from alternative splicing between sites located

Tumor-associated MUC1

TA-MUC1 differs from that expressed in normal cells, both in its biochemical features and its cellular distribution. Normally expressed MUC1 contains extensively branched Core 2 O-glycans (Figure 3A). By contrast, MUC1 in breast cancer cells mostly exhibits the Core 1 O-glycans [39] as loss of Core 2 β6-GlcNAc-transferase activity results in an absence of Core 2 O-glycans [40]. Additionally, TA-MUC1 is highly sialylated, which causes premature termination of chain elongation and formation of

Expression of TA-MUC1

MUC1 is overexpressed in cancer cells and the loss of cell polarity causes TA-MUC1 to be redistributed over the cell surface and within the cytoplasm (Figure 4) [3]. Lack of cell polarity also causes the redistribution of cell surface growth factors that are normally restricted to the basolateral surface of epithelial cells. Growth factors juxtaposed to MUC1 and intracellular kinases such as ZAP-70, PKC-γ, GSK-3β, and c-Src phosphorylate serine, tyrosine, and threonine residues on MUC1 CT (

The functional role of MUC1 in malignancy

The importance of MUC1 in disease progression is underscored by a study using mouse models of pancreatic and breast cancer. Muc1−/− mice expressing high levels of polyomavirus middle T antigen in the mammary gland spontaneously develop breast cancer but exhibit a substantial delay in disease progression and metastasis in comparison to Muc1+/+ mice [55]. Similarly, this trend was reported in a mouse model of spontaneous pancreatic ductal adenocarcinoma (PDA) 56, 57.

MUC1 as a cancer biomarker

Shed MUC1-N found in the circulation of cancer patients is used as a biomarker for cancer staging and monitoring relapse following therapy. For example, carbohydrate antigen 15.3 (CA 15.3, MUC1) and carbohydrate antigen 19.9 (CA 19.9, sLea antigen, found on several glycoproteins including MUC1) are commonly used for the detection of breast and pancreatic cancers, respectively 86, 87. Because MUC1-N is also released from stressed cells, the clinical utility of MUC1 measurement is confined to

Concluding remarks and future perspectives

Given the multifaceted functions of MUC1 in cancer, it is imperative to determine whether MUC1 plays an initiating role in carcinogenesis. We know that MUC1 is critical for the development of adenocarcinoma from preneoplastic PanIN lesions in the PDA mouse model 56, 57. In the absence of MUC1, PanIN lesions do not progress. Similarly, in the APCmin mouse of spontaneously developing colon polyps, MUC1 drives the polyps to become adenocarcinomas [101]. Thus, one can assume that MUC1 is crucial

Acknowledgments

We would like to acknowledge Dr Ian Marriott and Ms Tonya Bates for reviewing the manuscript for clarity.

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