β1,6-Branched Oligosaccharides Are Increased in Lymph Node Metastases and Predict Poor Outcome in Breast Carcinoma

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Abstract
Purpose: This study was designed to provide a comprehensive assessment on the role of β1,6-branched oligosaccharides in the metastasis and outcome of breast carcinoma. Generation of these structures on N-glycans is initiated by β1,6-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 β1,6-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 β1,6-branched oligosaccharides was directly associated with breast carcinoma nodal metastasis. Multivariate analyses revealed that β1,6-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 β1,6-N-acetylglucosaminyltransferase V activity and β1,6-branched oligosaccharides in breast carcinoma metastasis, and reemphasize the involvement, although poorly understood, of aberrant glycosylation in tumor progression.