Abstract
Abstract Aberrant glycosylation is a common feature of malignant change. Changes in mucin type O-linked glycosylation in breast cancer can result in the expression of truncated core 1-based sialylated glycans rather than the core 2-based glycans observed in normal mammary epithelium cells. This has been shown in part to be due to changes in the expression of glycosyltransferases including the upregulation of some sialyltransferases. Using the breast cancer cell line T47D we have shown that PGE2, one of the final products of the COX-2 pathway can induce the mRNA expression of the sialyltransferase, ST3Gal-I resulting in increased sialyltransferase activity demonstrated by a reduction in PNA lectin staining. Induction of COX-2 in the MDA-MB-231 breast cancer cell line also results in the increased expression of ST3Gal-I leading to increased sialylation of the substrate of ST3Gal-I, core1 Galβ1,3GalNAc. This effect on sialylation could be reversed by the selective COX-2 inhibitor celecoxib. The use of siRNA to knock-down COX-2 and over-expression of COX-2 in MDA-MD-231 confirmed the involvement of COX-2 in the upregulation of ST3Gal-I. Moreover, analysis of the expression of ST3Gal-I and COX-2 by 74 primary breast cancers showed a significant correlation between the two enzymes. COX-2 expression has been associated with a number of tumours including breast cancer where its expression is associated with poor prognosis. Thus these results suggest the intriguing possibility that some of the malignant characteristics associated with COX-2 expression may be by via the influence that COX-2 exerts on the glycosylation of tumour cells.
Highlights
Aberrant glycosylation is a common feature of breast cancer
Using the breast cancer cell line T47D, we have shown that PGE2, one of the final products of the cyclooxygenase-2 (COX-2) pathway, can induce the mRNA expression of the sialyltransferase ␣-2,3-sialyltransferase-3 (ST3Gal-I), resulting in increased sialyltransferase activity, demonstrated by a reduction in PNA lectin staining
To determine whether ST3Gal-I expression can be induced in T47D by PGE2, the cells were incubated with exogenous PGE2 (0.1 M) for 4 h, and the expression of ST3Gal-I was measured by Quantitative Real-time PCR (qRT-PCR)
Summary
Aberrant glycosylation is a common feature of breast cancer. Results: Cyclooxygenase-2 (COX-2), an enzyme associated with tumorigenesis in breast cancer, up-regulated the sialyltransferase ST3Gal-I. Changes in mucin-type O-linked glycosylation in breast cancer can result in the expression of truncated core 1-based sialylated glycans rather than the core 2-based glycans observed in normal mammary epithelium cells. This has been shown, in part, to be due to changes in the expression of glycosyltransferases, including the up-regulation of some sialyltransferases. A phase III clinical trial is underway to assess the adjuvant benefit of a selective COX-2 inhibitor, celecoxib, for the treatment of primary breast cancer [25] Given these data, we investigated the role of COX-2 in the control of the expression of the sialyltransferase ST3Gal-I in breast cancer. This is the first report of the control of ST3Gal-I expression in breast cancer
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