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Originally published In Press as doi:10.1074/jbc.M006523200 on December 15, 2000

J. Biol. Chem., Vol. 276, Issue 14, 11007-11015, April 6, 2001
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The Relative Activities of the C2GnT1 and ST3Gal-I Glycosyltransferases Determine O-Glycan Structure and Expression of a Tumor-associated Epitope on MUC1*

Martin DalzielDagger §, Caroline WhitehouseDagger §, Ian McFarlaneDagger , Inka Brockhausen||, Stephen Gschmeissner**, Tilo SchwientekDagger Dagger , Henrik ClausenDagger Dagger , Joy M. BurchellDagger , and Joyce Taylor-PapadimitriouDagger §§

From the Dagger  Imperial Cancer Research Fund, Breast Cancer Biology Group, 3rd Floor, Thomas Guy House, Guy's Hospital, London SE1 9RT, United Kingdom, || Department of Medicine, Division of Rheumatology, Queen's University, Etherington Hall, Room 1021, 96 Stuart Street, Kingston K7L 3N6, Ontario, Canada, ** Electron Microscopy Unit, Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom, and Dagger Dagger  School of Dentistry, Faculty of Health Sciences, University of Copenhagen, Norre Alle 20, DK 2200 Copenhagen N, Denmark

In breast cancer, the O-glycans added to the MUC1 mucin are core 1- rather than core 2-based. We have analyzed whether competition by the glycosyltransferase, ST3Gal-I, which transfers sialic acid to galactose in the core 1 substrate, is key to this switch in MUC1 glycosylation that results in the expression of the cancer-associated SM3 epitope. Of the three enzymes known to convert core 1 to core 2, by the addition of GlcNAc to GalNAc in core1 C2GnT1 is the dominant enzyme expressed in normal breast tissue. Expression of C2GnT1 is low or absent in around 50% of breast cancers, whereas expression of ST3Gal-I is consistently increased. Mapping of ST3Gal-I and C2GnT1 within the Golgi pathway showed some overlap. To examine functional competition, the enzymes were overexpressed in T47D cells, which normally make core 1-based structures, have no detectable C2GnT1 activity and express the SM3 epitope. Overexpression of C2GnT1 resulted in loss of binding of SM3 to MUC1, accompanied by a decrease in the GalNAc/GlcNAc ratio, indicative of a switch to core 2 structures. Transfection of a C2GnT1 expressing line with ST3Gal-I restored SM3 binding and reduced GlcNAc incorporation into MUC1 O-glycans. Thus, even when C2GnT1 is expressed, the O-glycans added to MUC1 become core 1-dominated structures, provided expression of ST3Gal-I is increased as it is in breast cancer.

* This work was supported by European Union Biotech Grant B104 CT96 0139.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Contributed equally and should be considered joint first authors.

Present address: Div. of Medical and Molecular Genetics, 8th Floor, Guy's Tower, Guy's Hospital, London SE1 9RT, UK.

§§ To whom correspondence should be addressed. Tel.: 44 20 7955 2310/4542; Fax: 44 20 7955 2027; E-mail: papadimi@icrf.icnet.uk.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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