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J. Biol. Chem., Vol. 281, Issue 6, 3586-3594, February 10, 2006

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The ST6GalNAc-I Sialyltransferase Localizes throughout the Golgi and Is Responsible for the Synthesis of the Tumor-associated Sialyl-Tn O-Glycan in Human Breast Cancer^*

Robert Sewell, Malin Bäckström¹, Martin Dalziel², Steven Gschmeissner^¶, Hasse Karlsson, Thomas Noll^||3, Jochem Gätgens^||, Henrik Clausen^**4, Gunnar C. Hansson¹, Joy Burchell, and Joyce Taylor-Papadimitriou⁵

From the Cancer Research-UK Breast Cancer Biology Group, 3rd Floor, Guy's Hospital, London SE1 9RT, United Kingdom, the Department of Medical Biochemistry, Göteborg University, 413 90 Gothenburg, Sweden, the ^¶Electron Microscopy Unit, Cancer Research-UK London Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom, the ^||Institute of Biochemistry Research Center, Juelich GmbH, D-52425 Juelich, Germany, and the ^**Department of Medical Biochemistry and Genetics Health Science Faculty, University of Copenhagen, DK-2200 Copenhagen, Denmark

The functional properties of glycoproteins are strongly influenced by their profile of glycosylation, and changes in this profile are seen in malignancy. In mucin-type O-linked glycosylation these changes can result in the production of mucins such as MUC1, carrying shorter sialylated O-glycans, and with different site occupancy. Of the tumor-associated sialylated O-glycans, the disaccharide, sialyl-Tn (sialic acid 2,6GalNAc), is expressed by 30% of breast carcinomas and is the most tumor-specific. The ST6GalNAc-I glycosyltransferase, which can catalyze the transfer of sialic acid to GalNAc, shows a highly restricted pattern of expression in normal adult tissues, being largely limited to the gastrointestinal tract and absent in mammary gland. In breast carcinomas, however, a complete correlation between the expression of RNA-encoding ST6GalNAc-I and the expression of sialyl-Tn is evident, demonstrating that the expression of sialyl-Tn results from switching on expression of hST6GalNAc-I. Endogenous or exogenous expression of hST6GalNAc-I (but not ST6GalNAc-II) always results in the expression of sialyl-Tn. This ability to override core 1/core 2 pathways of O- linked glycosylation is explained by the localization of ST6GalNAc-I, which is found throughout the Golgi stacks. The development of a Chinese hamster ovary (CHO) cell line expressing MUC1 and ST6GalNAc-I allowed the large scale production of MUC1 carrying 83% sialyl-Tn O-glycans. The presence of ST6GalNAc-I in the CHO cells reduced the number of O-glycosylation sites occupied in MUC1, from an average of 4.3 to 3.8 per tandem repeat. The availability of large quantities of this MUC1 glycoform will allow the evaluation of its efficacy as an immunogen for immunotherapy of MUC1/STn-expressing tumors.

Received for publication, November 2, 2005 , and in revised form, November 29, 2005.

^* This work was supported in part by Cancer Research-UK, by the European Commission(Grant QLRT-2002-02010), and by the Breast Cancer Campaign (Grant 2000:122). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by Assar Gabrielsson's foundation for cancer research, Lars Hierta's foundation, the Swedish Cancer Foundation, and the Swedish Research Council.

² Current address: Dept. of Biochemistry, University of Oxford, South Parks Road, OxfordOX1 3QU, United Kingdom.

³ Current address: Faculty of Technology, Universitaet Bielefeld, Universitaetsstrasse 25,P. O. Box 100131, Bielefeld 33501, Germany.

⁴ Supported by the Danish Cancer Society.

⁵ To whom correspondence should be addressed: Tel.: 44-20-7188-1472; Fax: 44-20-7188-0919; E-mail: joyce.taylor-papadimitriou{at}cancer.org.uk.

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