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ß1,6-Branched Oligosaccharides Are Increased in Lymph Node Metastases and Predict Poor Outcome in Breast Carcinoma

Authors' Affiliations: ¹ Department of Pathology, University of Massachusetts School of Medicine, Worchester, Massachusetts; Departments of ² Pathology and ³ Dermatology, and ⁴ Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut

Requests for reprints: John M. Pawelek, Department of Dermatology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8059. Phone: 203-785-4411; Fax: 203-785-7637; E-mail: john.pawelek{at}yale.edu.

Purpose: This study was designed to provide a comprehensive assessment on the role of ß1,6-branched oligosaccharides in the metastasis and outcome of breast carcinoma. Generation of these structures on N-glycans is initiated by ß1,6-N-acetylglucosaminyltransferase V and used by both myeloid cells and cancer cells in systemic migration.

Experimental Design: Tissue microarrays of >700 tumors (>400 patients; 30-year follow-up data) were stained through lectin histochemistry with leukocytic phytohemagglutinin (LPHA), a selective marker for ß1,6-branched oligosaccharides. Node-negative and node-positive primary tumors and patient-matched lymph node metastases were scored by blinded observers.

Results: Metastases stained at significantly greater intensities than did the patient-matched primary tumors (P < 0.0001), demonstrating for the first time that the abundance of ß1,6-branched oligosaccharides was directly associated with breast carcinoma nodal metastasis. Multivariate analyses revealed that ß1,6-branched oligosaccharides in primary tumors were a predictor of poor outcome, most notably in node-negative tumors, where an LPHA staining score of 3+ gave a risk factor of 3.3, independent of tumor size, nuclear grade, or patient age (P = 0.007).

Conclusions: The data firmly establish a role for ß1,6-N-acetylglucosaminyltransferase V activity and ß1,6-branched oligosaccharides in breast carcinoma metastasis, and reemphasize the involvement, although poorly understood, of aberrant glycosylation in tumor progression.

Key Words: N-glycosylation • GnT-V • tumor progression • Kaplan-Meier analyses • vesicular phenotype

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