O-linked mucin-type glycosylation in breast cancer

Abstract

Changes in mucin-type O-linked glycosylation are seen in over 90% of breast cancers where increased sialylation is often observed and a change from branched glycans to linear glycans is often seen. There are many mechanisms involved including increased/altered expression of glycosyltransferases and relocalisation to the endoplasmic reticulum of the enzymes responsible for the addition of the first sugar, N-acetyl-d-galactosamine. It is now becoming clear that these changes can contribute to tumour growth and progression by modulating the micro-environment through glycan-sensing lectins expressed on immune cells, by modulating interactions with tumour surface receptors and by binding to selectins. The understanding of how changes in mucin-type O-linked glycosylation influence tumour growth and progression reveals new potential targets for therapeutic intervention in the treatment of breast cancer.

Keywords: O-linked mucin-type glycosylation; breast cancer; glycosyltransferases; immunotherapy; lectins.

Figure 1.. Pathways of O-GaalNAc glycosylation in the normal and malignant mammary gland.

In the normal mammary gland epithelial cells O-GalNAc glycans are core 2-based and extension can occur from the Gal and the GlcNAc. COSMC is indicated under the T synthase as it acts as a private chaperone for this enzyme and hence is required for T synthase activity ([21], see text). In many breast cancers truncated mucin-type O-linked glycans are seen often terminating in sialic acid due to up-regulation of sialyltransferases [16]. However, in ER-ve breast cancer core 2-based glycans are expected to be present and may dominate due to the overexpression of the C1GALT1 and GCNT1 in ER-ve tumours compared with ER+ve breast cancers [20]. Symbols used are based on the nomenclature recommended in Varki et al. [79].

Figure 2.. Mucin-type O-GalNAc glycosylation is initiated in the Golgi.

(A) Normally O-GalNAc glycosylation is initiated in the Golgi. GalNAcTs are not confined to the cis-Golgi, and ST3GalI and C2GNT overlap to some degree [80]. (B) In the malignant cell some GalNAcTs can be relocated to the endoplasmic reticulum where normally unmodified serine/threonines in proteins can be modified with GalNAc by the ER-relocated GalNAcTs. This results in increasing the density of glycosylation and expression of Tn. This relocation process is termed the GALA pathway [24,32,33]. ST3GalI is overexpressed in 90% of breast cancers [16], and ST6GalNAcI is seen in 25% of breast cancers [34]. Changes in pH across the Golgi cisternae can also be observed in breast cancer [43,44]. For clarity only GalNAcTs, sialyltransferases and C2GNT are depicted.

Figure 3.. Mucin-type O-GalNAc glycosylation changes seen in breast cancer lead to increase in tumour growth and progression through a number of mechanisms.

O-GalNAc changes lead to novel interactions with lectins on immune cells including the binding of sialylated glycans to siglecs on monocytes, macrophages and NK cells. This includes the binding of MUC1-ST to siglec-9 on monocytes and macrophages and the binding of sialylated LacNAc (which can be carried on core 1 and core 2 branches) to siglec-7 on NK. Binding of Tn and STn to MGL on dendritic cells and macrophages is also observed. Expression of sLe^X can lead to binding to selectins on endothelial cells, and different core glycans can dictate how cancer cells respond to EGF binding. M, monocytes; MΦ, macrophages; TAM, tumour-associated macrophages; NK, natural killer cells; DC, dendritic cells; MGL, macrophage galactose-specific lectin; EGFR, epidermal growth factor receptor. Symbols for the glycans are as in Figure 1 with the addition of the red triangle for fucose.