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Papers In Press, published online ahead of print December 15, 2000
Breast Cancer Biology Group, Imperial Cancer Research Fund at Guys, London SE1 9RT
Corresponding Author: papadimi{at}icrf.icnet.uk
In breast cancer, the O-glycans added to the MUC1 mucin, are core 1 rather than core 2 based. We have analysed 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 which results in the expression of the cancer-associated SM3 epitope. Of the three enzymes known to convert core 1 to core 2 by addition of GlcNAc to GalNAc in core 1,C2GnT1 is the dominant enzyme expressed in normal breast tissue. Expression of C2GnT1 is reduced in some but not all breast cancers, while 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 over-expressed in T47D cells, which normally make core 1 based structures, have no detectable C2GnT1 activity and express the SM3 epitope. Over-expression 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.
J. Biol. Chem, 10.1074/jbc.M006523200
Submitted on July 21, 2000
Revised on December 15, 2000
Accepted on December 15, 2000
The relative activities of the C2GnT1 and ST3GalI glycosyltransferases determine O-glycan structure and expression of a tumour-associated epitope on MUC1
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