title: Mechanisms underlying aberrant glycosylation of MUC1 mucin in breast cancer cells.
abstract: The product of the MUC1 gene, the polymorphic epithelial mucin (PEM) is aberrantly glycosylated in breast and other carcinomas, resulting in exposure of normally cryptic peptide epitopes. PEM expressed by breast cancer cells contains more sialylated O-glycans and has a lower GlcNAc content than that expressed by normal cells. The exposure of peptide epitopes is thus thought to be due to the sugar side chains being shorter on the tumour-associated mucin. To investigate possible mechanisms underlying the different pattern of glycosylation in breast cancer cells, we analysed the pathways involved in the biosynthesis of O-glycan chains of mucins in normal and cancerous mammary epithelial cells. An immortalized mammary epithelial cells line originating from normal human milk. MTSV1-7, and three human breast cancer cell lines, BT20, MCF-7 and T47D, were studied. Glycosyltransferase activities assembling, elongating and terminating O-glycan core-1 [Gal beta 1-3GalNAc alpha-R] and core-2 [GlcNac beta 1-6 (Gal beta 1-3) GalNAc alpha-R] were present in the normal mammary cell line. Many of the glycosyltransferase activities were also expressed at variable levels in breast cancer cells. However, a sialyltransferase activity (CMP-sialic acid Gal beta 1-3GalNAc alpha 3-sialyltransferase) was increased several fold in all three cancer cell lines. Moreover, mammary cancer cell lines BT20 and T47D have lost the ability to synthesize core-2, as shown by the lack of UDP-GlcNAc: Gal beta 1-3GalNAc (GlcNAc to GalNAc) beta 6-GlcNAc-transferase activity, which corresponded to the absence of the mRNA transcript. However, MCF-7 breast cancer cells expressed this enzyme. Thus, the mechanism for the exposure of peptide epitopes in BT20 and T47D cells is proposed to be the loss of core-2 branching leading to shorter, sialylated O-glycan chains. A different mechanism is proposed for MCF-7 breast cancer cells.
authors.affiliation: Biochemistry Department, Hospital for Sick Children, Toronto, Canada.
authors.forename: I
authors.initials: I
authors.lastname: Brockhausen
authors.forename: J M
authors.initials: JM
authors.lastname: Yang
authors.forename: J
authors.initials: J
authors.lastname: Burchell
authors.forename: C
authors.initials: C
authors.lastname: Whitehouse
authors.forename: J
authors.initials: J
authors.lastname: Taylor-Papadimitriou
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism*; D002460:Cell Line; D005260:Female; D005647:Fucosyltransferases / Q000378:metabolism; D006031:Glycosylation; D016695:Glycosyltransferases / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000378:metabolism*; D017350:N-Acetylgalactosaminyltransferases / Q000378:metabolism; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D012799:Sialyltransferases / Q000378:metabolism; D015238:Sulfotransferases / Q000378:metabolism
chemical_list: D018396:Mucin-1; D009363:Neoplasm Proteins; D016695:Glycosyltransferases; D005647:Fucosyltransferases; D017350:N-Acetylgalactosaminyltransferases; D017351:N-Acetylglucosaminyltransferases; D012799:Sialyltransferases; D015238:Sulfotransferases