In this study, we have showed that GCNT2, a gene-encoding glucosaminyl (N-acetyl)
transferase 2,
I-branching enzyme, is overexpressed in highly metastatic
breast cancer cell lines of human and mouse origin and basal-like
breast tumor samples. GCNT2 expression is also significantly correlated to the metastatic phenotype in
breast tumor samples. Functional studies showed that ectopic expression of GCNT2 enhances cell detachment, adhesion to endothelial cells, cell migration and invasion in vitro, and lung
metastasis of
breast cancer cells in vivo. Knockdown of GCNT2 expression decreases cell migration and invasion in vitro and lung
metastasis in vivo. We have further shown the involvement of GCNT2 in the epithelial-to-mesenchymal transition (EMT). Specifically, the expression of
E-cadherin is significantly changed upon GCNT2 expression at the
protein level but not at the
RNA level. Moreover, we have shown that GCNT2 is a direct target of the TGF-β-smad pathway and that change in GCNT2 expression modulates EMT induced by TGF-β1 treatment. Finally, we have shown that diminution of the
glycosyltransferase activity of I-branching β-1, 6-N-acetylglucosaminyl
transferase 2 (GCNT2) abrogates its cell migration and invasion-promoting function and synergistic effect with TGF-β to induce EMT. Our study for the first time showed that GCNT2 is a novel gene contributing to
breast cancer metastasis with preferential expression in basal-like
breast cancer. Moreover, we discovered that involvement of GCNT2 in EMT and TGF-β signaling, and further glycosylation modification of
E-cadherin by GCNT2, are the underlying integrative mechanisms for
breast cancer metastasis, implying that blocking TGF-β/GCNT2 signaling is a promising approach for targeting metastatic
breast cancer.