title: Relevance of βGal-βGalNAc-containing glycans and the enzymes involved in their synthesis for invasion and survival in breast cancer patients.
abstract: To study the influence of glycosylation on breast cancer progression by analyses on glycan, mRNA, and protein level. For detection of glycan structures, we performed lectin histochemistry with five lectins of different specificity (UEA-1, HPA, GNA, PNA, and PHA-L) on a tissue microarray with >400 breast cancer samples. For comparison, mRNA expression of glycosylation enzymes involved in the synthesis of HPA and PNA binding glycostructures (GALNT family members and C1GALT1) was analyzed in microarray data of 194 carcinomas. Additionally, C1GALT1 protein expression was analyzed by Western blot analysis in 106 tumors. Correlations with clinical and histological parameters including recurrence-free (RFS) and overall survival (OAS) were calculated. Positive binding of four lectins (HPA, GNA, PNA, and PHA-L) correlated significantly with parameters involved in tumor metastasis, namely lymphangiosis, vascular invasion, lymph node involvement, and presence of disseminated tumor cells in bone marrow. HPA and PNA binding also showed a negative prognostic impact in our cohort. Correspondingly, high expression of C1GALT1, GALNT1, GALNT8, or GALNT14 mRNA and C1GALT1 protein correlated significantly with shorter OAS. Notably, combined overexpression of C1GALT1/GALNT1 or C1GALT1/GALNT8 mRNA was associated with a significantly reduced OAS (HR 3.15 and 2.73) and RFS (HR 2.01 and 1.94), pointing to an additive influence of these enzymes. This prognostic impact retained significance in multivariate analysis including classical prognostic markers. Our data indicate that glycan structures containing βGal-βGalNAc residues and the enzymes involved in their synthesis play a role in breast cancer progression, at least partly by their promoting influence on haematogenic and lymphatic spread.
authors.affiliation: Department of Gynecology, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany, milde@uke.de.
authors.forename: Karin
authors.initials: K
authors.lastname: Milde-Langosch
authors.forename: Dina
authors.initials: D
authors.lastname: Schütze
authors.forename: Leticia
authors.initials: L
authors.lastname: Oliveira-Ferrer
authors.forename: Harriet
authors.initials: H
authors.lastname: Wikman
authors.forename: Volkmar
authors.initials: V
authors.lastname: Müller
authors.forename: Patrick
authors.initials: P
authors.lastname: Lebok
authors.forename: Klaus
authors.initials: K
authors.lastname: Pantel
authors.forename: Christine
authors.initials: C
authors.lastname: Schröder
authors.forename: Isabell
authors.initials: I
authors.lastname: Witzel
authors.forename: Udo
authors.initials: U
authors.lastname: Schumacher
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D005260:Female; D005700:Galactosyltransferases / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D037102:Lectins / Q000235:genetics; D008875:Middle Aged; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics / Q000378:metabolism*; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011134:Polysaccharides / Q000378:metabolism*; D011485:Protein Binding; D016896:Treatment Outcome; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D014408:Biomarkers, Tumor; D005700:Galactosyltransferases; D037102:Lectins; D017350:N-Acetylgalactosaminyltransferases; D011134:Polysaccharides; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C505293:C1GALT1 protein, human