Control of expression of glycosyltransferases involved in O-linked glycosylation in breast cancer.

Abstract

Aberrant glycosylation is a common phenotypic change observed in malignancy. Changes in mucin-type O-glycosylation in breast cancer can result in the expression of truncated core 1-based sialylated glycans rather than core 2-based glycans found in the normal gland. This is partly due to changes in the expression of glycosyltransferases. C2GnT1 expression, the glycosyltransferase that initiates branching in normal mammary epithelial cells, can be decreased in tumour cells while, in contrast, the expression of the sialyltransferase ST3Gal-l, which causes chain termination, increases in breast cancer. When dendritic cells mature, prior to migration to lymph nodes, their O-glycosylation changes by decreasing C2GnT1 expression and increasing ST3Gal-l expression. This can be controlled by PGE2, the major product of COX-2. The project described in this thesis investigated the control by PGE2/COX-2 of ST3Gal-l and C2GnT1 expression in breast carcinomas. Importantly, COX-2 is normally only expressed during inflammation but is found to be upregulated by many carcinomas including those of the breast. In the breast cancer line T47D, mRNA expression of ST3Gal-l was induced by PGE2, resulting in increased sialyltransferase activity. Induction of COX-2 in the MDA-MB-231 breast cancer cell line also resulted in increased expression of ST3Gal-l and increased sialylation of the ST3Gal-l substrate. This effect on sialylation could be reversed by the selective COX-2 inhibitor celecoxib. The use of siRNA to knock-down COX-2 and the over-expression of COX-2 in MDA-MD-231 confirmed the involvement of COX-2 in the upregulation of ST3Gal-l. Moreover, analysis of the expression of ST3Gal-l and COX-2 in 78 primary breast cancers showed a significant correlation between the two enzymes.
COX-2 expression in breast cancer has been associated with poor prognosis. Thus these results suggest the intriguing possibility that some of the malignant characteristics associated with COX-2 may be via the influence that COX-2 exerts on the glycosylation of tumour cells.

Date of Award	2013
Original language	English
Awarding Institution	King's College London
Supervisor	Joy Burchell (Supervisor) & Anne Ridley (Supervisor)