Core-Fucosylated Tetra-Antennary N-Glycan Containing A Single N-Acetyllactosamine Branch Is Associated with Poor Survival Outcome in Breast Cancer.

Harmin Herrera,Joelle N Zambrano,Elizabeth G Hill,Tinslee Dilday,Danielle Scott,Allison Uber,Anand S Mehta,Peggi M Angel,Elizabeth S Yeh,Richard R Drake,Mengjun Wang

doi:10.3390/ijms20102528

Abstract

(1) Glycoproteins account for ~80% of proteins located at the cell surface and in the extracellular matrix. A growing body of evidence indicates that α-L-fucose protein modifications contribute to breast cancer progression and metastatic disease. (2) Using a combination of techniques, including matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) based in cell and on tissue imaging and glycan sequencing using exoglycosidase analysis coupled to hydrophilic interaction ultra-high performance liquid chromatography (HILIC UPLC), we establish that a core-fucosylated tetra-antennary glycan containing a single N-acetyllactosamine (F(6)A4G4Lac1) is associated with poor clinical outcomes in breast cancer, including lymph node metastasis, recurrent disease, and reduced survival. (3) This study is the first to identify a single N-glycan, F(6)A4G4Lac1, as having a correlation with poor clinical outcomes in breast cancer.

Highlights

Fucosylation is a relatively well-defined biomarker for progression in many human cancers; for example, pancreatic and hepatocellular carcinoma [1,2,3,4,5,6,7,8], but its role in breast cancer is much less well defined
(2) Using a combination of techniques, including matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) based in cell and on tissue imaging and glycan sequencing using exoglycosidase analysis coupled to hydrophilic interaction ultra-high performance liquid chromatography (HILIC UPLC), we establish that a core-fucosylated tetra-antennary glycan containing a single N-acetyllactosamine (F(6)A4G4Lac1) is associated with poor clinical outcomes in breast cancer, including lymph node metastasis, recurrent disease, and reduced survival
Using a combination of techniques including matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) based in cell and on tissue imaging and glycan sequencing using exoglycosidase analysis coupled to hydrophilic interaction ultra-high performance liquid chromatography (HILIC UPLC), we establish that a core-fucosylated tetra-antennary glycan containing a single N-acetyllactosamine branch is present in 4T1 cells, as well as human breast tumor tissues using tumor microarrays (TMA)

Summary

Introduction

Fucosylation is a relatively well-defined biomarker for progression in many human cancers; for example, pancreatic and hepatocellular carcinoma [1,2,3,4,5,6,7,8], but its role in breast cancer is much less well defined. Fucose is exclusively used in the L-configuration (i.e., α-l-fucose). It is added to proteins in three major configurations: Core (an α-1,6-linkages to the core N-acetylglucosamine adjacent to asparagine), O-linked (on serine or threonine), and terminal/subterminal positions along the sugar chain. Thirteen major fucosylation related gene products have been identified. These are FUT1-11, POFUT1, and POFUT2, where FUT1-7, 9-11 regulate terminal/subterminal (outer arm) fucosylation, FUT8 regulates core fucosylation, and POFUT1 and POFUT2 regulate O-linked fucosylation. FUT8, POFUT1, and POFUT2 are the only three genes that are required for development and genetic knockout models demonstrate that loss of each gene results in lethal abnormalities, including severe growth retardation and defects [9,10,11,12,13]

Methods

Results

Discussion

Conclusion