Abstract
FUT1 and FUT2 encode alpha 1, 2-fucosyltransferases which catalyze the addition of alpha 1, 2-linked fucose to glycans. Glycan products of FUT1 and FUT2, such as Globo H and Lewis Y, are highly expressed on malignant tissues, including breast cancer. Herein, we investigated the roles of FUT1 and FUT2 in breast cancer. Silencing of FUT1 or FUT2 by shRNAs inhibited cell proliferation in vitro and tumorigenicity in mice. This was associated with diminished properties of cancer stem cell (CSC), including mammosphere formation and CSC marker both in vitro and in xenografts. Silencing of FUT2, but not FUT1, significantly changed the cuboidal morphology to dense clusters of small and round cells with reduced adhesion to polystyrene and extracellular matrix, including laminin, fibronectin and collagen. Silencing of FUT1 or FUT2 suppressed cell migration in wound healing assay, whereas FUT1 and FUT2 overexpression increased cell migration and invasion in vitro and metastasis of breast cancer in vivo. A decrease in mesenchymal like markers such as fibronectin, vimentin, and twist, along with increased epithelial like marker, E-cadherin, was observed upon FUT1/2 knockdown, while the opposite was noted by overexpression of FUT1 or FUT2. As expected, FUT1 or FUT2 knockdown reduced Globo H, whereas FUT1 or FUT2 overexpression showed contrary effects. Exogenous addition of Globo H-ceramide reversed the suppression of cell migration by FUT1 knockdown but not the inhibition of cell adhesion by FUT2 silencing, suggesting that at least part of the effects of FUT1/2 knockdown were mediated by Globo H. Our results imply that FUT1 and FUT2 play important roles in regulating growth, adhesion, migration and CSC properties of breast cancer, and may serve as therapeutic targets for breast cancer.
Highlights
Glycoconjugates have long been recognized as essential components of many living organisms
In light of the impact of FUT1 and FUT2 on cancer stem cells (CSC) and cell metastasis, we investigated the role of FUT1 and FUT2 in epithelial-mesenchymal transition (EMT), which was considered a hallmark of CSC and metastasis
Exogenous addition of Globo H-ceramide promoted cell adhesion in T47D cells expressing shLuc, but could not ameliorate the inhibitory effect of FUT2 knockdown on Discussion We have demonstrated the important roles of FUT1 and FUT2 in breast cancer as evidenced by their regulation of cell morphology, proliferation, adhesion, migration, and mammosphere formation in vitro and tumorigenicity and metastasis in vivo
Summary
Glycoconjugates have long been recognized as essential components of many living organisms. A number of studies have documented the roles of glycoconjugates in a variety of diseases such as viral and bacterial infection, inflammation, autoimmune dysfunction, or cancer metastasis[1]. Specific glycan structures have been reported to correlate with breast tumor progression, such. Among these tumor associated glycans, the terminal alpha 1, 2-linked fucose of Lewisy and Globo H are synthesized by alpha 1, 2 fucosyltransferase, FUT1 and FUT2, in human[6,7]. In addition to breast cancer, altered cell surface alpha 1, 2-fucosylated glycans have been found in a variety of malignancies such as cancers of colon, pancreas, endometrium, cervix, bladder, lung and choriocarcinoma
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