Up-regulation of C1GALT1 promotes breast cancer cell growth through MUC1-C signaling pathway

Abstract

Aberrant glycosylation is frequently observed in cancers. Core 1 β1,3-galactosyltransferase (C1GALT1) is an exclusive enzyme in humans that catalyzes the biosynthesis of core 1 O-glycan structure, Gal-GalNAc-O-Ser/Thr, whose expression is commonly up-regulated during tumorigenesis. Little is known about the function of C1GALT1 in breast cancer. This study aims to determine the correlation between C1GALT1 expression and breast cancer clinicopathological features and roles of C1GALT1 in breast cancer malignant phenotypes. Public databases and our data showed that C1GALT1 mRNA and C1GALT1 protein are frequently up-regulated in breast cancer; and increased C1GALT1 expression correlates with higher histological grade and advanced tumor stage. Overexpression of C1GALT1 enhanced breast cancer cell growth, migration, and invasion in vitro as well as tumor growth in vivo. Conversely, C1GALT1 knockdown suppressed these malignant phenotypes. Furthermore, C1GALT1 modulates O-glycan structures on Mucin (MUC) 1 and promotes MUC1-C/β-catenin signaling in breast cancer cells. These findings suggest that C1GALT1 enhances breast cancer malignant progression through promoting MUC1-C/β-catenin signaling pathway. Unveiling the function of C1GALT1 in breast cancer opens new insights to the roles of C1GALT1 and O-glycosylation in tumorigenesis and renders the potential of C1GALT1 as a target of novel therapeutic agent development.

Loss of Core 1-derived O-Glycans Decreases Breast Cancer Development in Mice

“…Our results are consistent with recent reports that show higher C1galt1 gene expression in human breast cancer relative to non-cancerous breast tissue (8,9). In addition, increased C1galt1 expression in tumor tissue has been associated with enhanced Muc1 function and advanced tumor stages (9).…”

“…In addition, increased C1galt1 expression in tumor tissue has been associated with enhanced Muc1 function and advanced tumor stages (9). Our study provides evidence that elimination of core 1 O-glycosylation alters the expression pattern of Muc1 in both non-transformed and transformed mammary epithelial cells in vivo and results in decreased Muc1 signaling associated with cell proliferation.…”

“…Lack of C1galt1 activity results in exposure of Tn (1,6). In human breast cancer, higher C1galt1 gene expression has been found in ductal breast carcinomas when compared with non-cancerous tissues (8,9). Higher C1galt1 expression in tumor tissue is associated with advanced tumor stages and poor survival in breast cancer patients (9,10).…”

“…In human breast cancer, higher C1galt1 gene expression has been found in ductal breast carcinomas when compared with non-cancerous tissues (8,9). Higher C1galt1 expression in tumor tissue is associated with advanced tumor stages and poor survival in breast cancer patients (9,10). Yet, the in vivo role of core 1 O-glycan and its derivatives (core 1-derived O-glycans) in breast tumor development remains to be defined.…”

C1GALT1 Seems to Promote In Vitro Disease Progression in Ovarian Cancer

“…17,18 Moreover, we recently reported that C1GALT1 alters O-glycans on hepatocyte growth factor receptor, also known as MET, and enhances MET dimerization in hepatocellular carcinoma 19 ; modifies O-glycans on fibroblast growth factor receptor 2 and its downstream signaling involved in colorectal cancer malignant phenotypes 20 ; and enhances breast cancer malignant progression by modulating O-glycans on Mucin (MUC) 1 and promoting MUC1-C/Acatenin signaling pathway. 21 Although C1GALT1 and mucintype O-glycosylation have been shown to play crucial roles in a variety of biologic functions, the roles of C1GALT1 in ovarian cancer remain unclear.…”