A Transfected Sialyltransferase That Is Elevated in Breast Cancer and Localizes to the medial/trans-Golgi Apparatus Inhibits the Development of core-2–based O-Glycans

Whitehouse, Caroline; Burchell, Joy; Gschmeissner, Stephen; Brockhausen, Inka; Lloyd, Kenneth O.; Taylor-Papadimitriou, Joyce

The change in glycosylation pattern seen in breast cancer also relates specifically to the studies on the MUC1 mucin as a potential target antigen in active specific immu-notherapy of breast cancer. The extracellular domain of the MUC1 glycoprotein is made up largely of tandem repeats of 20 amino acids: 25-100 depending on the allele (Gendler et al., 1990) , and each repeat contains potential glycosylation sites (Nishimori et al., 1994; Stadie et al., 1995) . The antigenic profile of the mucin is therefore dramatically altered when the composition of the O-glycans added is changed from being core-2 based to the simpler, shorter, and more heavily sialylated glycans found on the tumor mucin. Indeed, both humoral and cellular responses to the MUC1 mucin have been observed in breast cancer patients, who show some specificity for the aberrantly glycosylated mucin expressed by the tumor cells (von Mensdorff-Pouilly et al., 1996; Magarian et al., 1993) . Our findings show that it may be possible to produce the appropriate glycoform of the mucin in recombinant form by manipulating the glycosyltransferases in the producer cell. CHO cells, widely used for the production of recombinant proteins, do not in fact express the core-2 ␤1,6 GlcNAc T (Li et al., 1996) and have been reported to synthesize short O-glycans (Oheda et al., 1988) . It may then be relatively simple to produce the MUC1 antigen in these cells with minimal manipulation. Furthermore, although the results presented here would support the hypothesis that the distributions of the core-2 ␤1,6 GlcNAc transferase and the ␣2,3 sialyltransferase show some overlap, it will be important to confirm this by detailed mapping of the position of the ␤1,6 GlcNAc transferase.