Tumour-associated carbohydrate antigens in breast cancer

Abstract

Glycosylation changes that occur in cancer often lead to the expression of tumour-associated carbohydrate antigens. In breast cancer, these antigens are usually associated with a poor prognosis and a reduced overall survival. Cellular models have shown the implication of these antigens in cell adhesion, migration, proliferation and tumour growth. The present review summarizes our current knowledge of glycosylation changes (structures, biosynthesis and occurrence) in breast cancer cell lines and primary tumours, and the consequences on disease progression and aggressiveness. The therapeutic strategies attempted to target tumour-associated carbohydrate antigens in breast cancer are also discussed.

Figure 1

Pathways of biosynthesis of O-glycans in normal and cancer breast epithelial cells. All of these transfer reactions are catalysed in the Golgi apparatus. Enzymes involved in the pathways are indicated in italic font next to the arrows. Various mechanisms are illustrated by which O-glycans expressed in normal cells (bottom left) can be turned down to shorter and sialylated species. First, the enzymes involved in extended O-glycans can be downregulated or mutated (downward white arrows) in cancer cells, leading to a decrease or an absence of extended structures and revealing previously masked precursors such as T and Tn antigens. Alternatively or concomitantly, overexpression of diverse sialyltransferases (upward white arrows) can compete with the enzymes of normal extension and generate truncated sialylated structures (right column). This competition can occur at different levels of the extension pathway and produce the sialylated structures of each precursor (that is, sialyl-Thomsen-nouvelle (sTn) antigen, sialyl-Thomsen-Friedenreich (sialyl-T or sialyl-TF) antigen (or sialylated Core1) and sialylated Core2 O-glycans). Gal, Galactose, GalNAc, N-acetylgalactosamine; GlcNAc, N-acetylglucosamine; Neu5Ac, N-acetylneuraminic acid; Fuc, fucose. Linkages (anomery and carbons involved) are only indicated the first time they appear along the pathway. N, various numbers (2 to 10) of repeats of lactosamine units (Gal β1-3/4GlcNAc).

Figure 2

Short O-glycans observed in breast epithelial cells during carcinogenesis. Structures of short O-glycans observed in breast epithelial cells during carcinogenesis and their binding to Arachis hypogea agglutinin/peanut lectin (PNA) lectin or HH8 mAb, and to Amaranthus caudatus agglutinin (ACA) or Artocarpus integrifolia agglutinin/jacalin (AIA). T or TF, Thomsen-Friedenreich; Tn, Thomsen-nouvelle.

Figure 3

Biosynthesis of Lewis antigens. Lewis antigens derive from the substitution of type 1 (Galβ1-3GlcNAc) or type 2 (Galβ1-4GlcNAc) disaccharide sequences by fucose and sialic acid residues. Name of the antigen is indicated next to the glycan structure. Names of the main enzymes involved in the biosynthetic pathways are indicated in italics. Arrows, antigens and enzymes altered in breast cancers.

Figure 4

Biosynthesis of gangliosides. The action of ST3Gal V (G_M3 synthase), ST8Sia I (G_D3 synthase) and ST8Sia V (G_T3 synthase) leads to the biosynthesis of the precursor of a-series, b-series and c-series gangliosides, respectively. The o-series gangliosides are directly synthesized from lactosylceramide (LacCer). Elongation of complex gangliosides is performed by the sequential action of N-acetyl-galactosaminyltransferase (β4-GalNAc T1), galactosyltransferase (β3-GalT4) and sialyltransferases (ST3Gal I, ST3Gal II and ST8Sia V).