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Glycobiology Advance Access published online on September 25, 2008
Glycobiology, doi:10.1093/glycob/cwn095
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© The Author 2008. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

A strategy to reveal potential glycan markers from serum glycoproteins associated with breast cancer progression

Umi M. Abd Hamid1,2, Louise Royle1,3, Radka Saldova1,2, Catherine M. Radcliffe1,4, David J. Harvey1, Sarah J. Storr6, Maria Pardo1,5, Robin Antrobus1, Caroline J. Chapman6, Nicole Zitzmann1, John F. Robertson6, Raymond A. Dwek1 and Pauline M. Rudd1,2

1 Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, OX1 3QU, UK
6 Tumor Immunology Group, University of Nottingham, Division of Breast Surgery, Nottingham City Hospital, Hucknall Road, Nottingham, NG5 1PB, UK

Correspondence address: Dublin-Oxford Glycobiology Laboratory, NIBRT, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland. Phone: (+353) 1716 6728 Fax: (+353) 1716 6728 Email address: pauline.rudd{at}nibrt.ie

Received on June 20, 2008; accepted on September 23, 2008

Aberrant glycosylation on glycoproteins that are either presented on the surface or secreted by cancer cells, is a potential source of disease biomarkers and provides insights into disease pathogenesis. N-glycans of the total serum glycoproteins from advanced breast cancer patients and healthy individuals were sequenced by HPLC with fluorescence detection coupled with exoglycosidase digestions and mass spectrometry. We observed a significant increase in a tri-sialylated tri-antennary glycan containing {alpha}1,3-linked fucose which forms part of the sialyl Lewis x epitope. Following digestion of the total glycan pool with a combination of sialidase and β-galactosidase, we segregated and quantified a digestion product, a mono-galactosylated tri-antennary structure containing {alpha}1,3-linked fucose. We compared breast cancer patients and controls, and detected a two-fold increase of this glycan marker in patients. In ten patients monitored longitudinally we showed a positive correlation between the glycan marker and disease progression and also demonstrated its potential as a better indicator of metastasis compared to the currently used biomarkers, CA 15–3 and carcinoembryonic antigen (CEA). A pilot glycoproteomic study of advanced breast cancer serum highlighted acute-phase proteins {alpha}1–acid glycoprotein, {alpha}1-antichymotrypsin and haptoglobin β-chain as contributors to the increase in the glycan marker which, when quantified from each of these proteins, marked the onset of metastasis in advance of the CA 15–3 marker. These preliminary findings suggest that specific glycans and glycoforms of proteins may be candidates for improved markers of breast cancer.

Key words: breast cancer / N-linked glycans / acute-phase proteins / sLex / biomarker

2 Current address: Dublin-Oxford NIBRT Glycobiology Laboratory, NIBRT, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland

3 Current address: Ludger Ltd, Culham Science Centre, Abingdon, Oxfordshire OX14 3EB, UK

4 Current address: Lonza Biologics plc, 228 Bath Road, Slough, SL1 4DX, UK

5 Current address: Laboratorio de Endocrinología Molecular, Facultad de Medicina, Universidade de Santiago de Compostela, Rua San Francisco s/n, 15782 Santiago de Compostela, Spain


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