MUC4, also known as sialomucin complex (SMC), is a transmembrane glycoprotein. It consists of two subunits, ASGP-1 and ASGP-2, derived from a single gene. MUC4 is expressed in many epithelia, serving as a protective agent for them. It can act as a steric barrier on the apical cell surface and its soluble form helps with epithelial protection and lubrication. The transmembrane subunit ASGP-2 can function as an intramembrane ligand for the receptor tyrosine kinase ErbB2, regulating phosphorylation and apoptosis [2,4].

In pancreatic cancer, abrogation of MUC4 expression in in vitro, ex vivo or in vivo xenograft models reduces proliferation and metastasis of cancer cells and enhances sensitivity to therapeutic agents, suggesting its utility as a therapeutic target [1]. In HER2-positive breast cancer mouse models, deletion of Muc4 suppresses metastatic efficiency, as Muc4-knockout tumor cells are poorly associated with platelets and white blood cells that support circulating tumor cell viability [3].

In conclusion, MUC4 plays crucial roles in epithelial protection and in cancer-related processes such as tumorigenicity, metastasis, and therapy resistance. Gene-knockout mouse models have revealed its significance in pancreatic and breast cancer, providing insights for potential targeted therapies and immunotherapies.

References:

1. Gautam, Shailendra K, Kumar, Sushil, Cannon, Andrew, Batra, Surinder K, Jain, Maneesh. 2017. MUC4 mucin- a therapeutic target for pancreatic ductal adenocarcinoma. In Expert opinion on therapeutic targets, 21, 657-669. doi:10.1080/14728222.2017.1323880. https://pubmed.ncbi.nlm.nih.gov/28460571/

2. Carraway, Kermit L, Theodoropoulos, George, Kozloski, Goldi A, Carothers Carraway, Coralie A. . Muc4/MUC4 functions and regulation in cancer. In Future oncology (London, England), 5, 1631-40. doi:10.2217/fon.09.125. https://pubmed.ncbi.nlm.nih.gov/20001800/

3. Dreyer, Courtney A, VanderVorst, Kacey, Free, Savannah, Rowson-Hodel, Ashley, Carraway, Kermit L. 2021. The role of membrane mucin MUC4 in breast cancer metastasis. In Endocrine-related cancer, 29, R17-R32. doi:10.1530/ERC-21-0083. https://pubmed.ncbi.nlm.nih.gov/34726614/

4. Carraway, Kermit L, Perez, Aymee, Idris, Nebila, Zhang, Jin, Carraway, Coralie A Carothers. . Muc4/sialomucin complex, the intramembrane ErbB2 ligand, in cancer and epithelia: to protect and to survive. In Progress in nucleic acid research and molecular biology, 71, 149-85. doi:. https://pubmed.ncbi.nlm.nih.gov/12102554/