The membrane mucin MUC4 and its role in breast cancer progression and metastasis

MUC4 (called Muc4/sialomucin complex or SMC in rat), a transmembrane mucin, is a non-covalently linked heterodimeric protein complex composed of the two subunits MUC4alpha and MUC4beta arising from a single transcript. MUC4alpha contains the hallmark O-glycosylation domain characteristic of mucins. MUC4beta possesses a single transmembrane segment and a cytosolic domain of ∼20 amino acids. MUC4 expression is found in a variety of well-differentiated tissues and aberrant expression has also been reported in variety of carcinomas.;In these studies, Muc4 expression in human A375 melanoma cells and MCF7 breast cancer cells confers resistance to apoptosis induced by a variety of insults. Mapping experiments revealed that the O-glycosylation and cytosolic domains of Muc4 are dispensable for its anti-apoptotic activity and for potentiation of signaling by ErbB2. Knockdown of endogenous MUC4 in JIMT-1 breast cancer cells sensitizes cells to apoptosis. While MUC4 in JIMT-1 cells engages ErbB2, its anti-apoptotic mechanism in MCF7 and A375 cells appears to be independent of ErbB2. However, Muc4 expression in all cell lines culminates in the phosphorylation and inactivation of the pro-apoptotic protein Bad and the elevation of the pro-survival protein Bcl-xL.;MUC4 can additionally promote events associated with the initiation of carcinoma in colony forming soft agar assays. Overexpression of human MUC4/Y, a tumor-associated splice variant of MUC4 lacking the O-glycosylation domain, is sufficient to disrupt normal development of immortalized MCF10A human breast epithelial cells grown in three-dimensional culture by promoting survival and proliferative capacities of centrally-localized acinar cells. Likewise, knockdown of endogenous MUC4 in JIMT-1 human breast cancer cells suppresses cellular proliferation, survival, and growth in three-dimensional culture.;To assess the potential involvement of MUC4 in breast cancer progression and metastasis, we investigated MUC4 expression in normal breast tissue and primary and metastatic tumors. Surprisingly, we observed by immunoblotting and immunohistochemistry that MUC4 levels are suppressed in the majority (57%, p<0.001) of primary tumors relative to patient-matched normal tissue. Additionally, lymph node metastatic lesions from 38% (p<0.05) of patients expressed higher protein MUC4 levels than patient-matched primary tumors.;Taken together, these studies enhance our understanding of MUC4 during breast cancer progression and metastasis.