Genes that mediate breast cancer metastasis to the brain Journal Article
| Authors: | Bos, P. D.; Zhang, X. H. F.; Nadal, C.; Shu, W.; Gomis, R. R.; Nguyen, D. X.; Minn, A. J.; van de Vijver, M. J.; Gerald, W. L.; Foekens, J. A.; Massague, J. |
| Article Title: | Genes that mediate breast cancer metastasis to the brain |
| Abstract: | The molecular basis for breast cancer metastasis to the brain is largely unknown. Brain relapse typically occurs years after the removal of a breast tumour, suggesting that disseminated cancer cells must acquire specialized functions to take over this organ. Here we show that breast cancer metastasis to the brain involves mediators of extravasation through non-fenestrated capillaries, complemented by specific enhancers of blood-brain barrier crossing and brain colonization. We isolated cells that preferentially infiltrate the brain from patients with advanced disease. Gene expression analysis of these cells and of clinical samples, coupled with functional analysis, identified the cyclooxygenase COX2 (also known as PTGS2), the epidermal growth factor receptor (EGFR) ligand HBEGF, and the α2,6-sialyltransferase ST6GALNAC5 as mediators of cancer cell passage through the blood-brain barrier. EGFR ligands and COX2 were previously linked to breast cancer infiltration of the lungs, but not the bones or liver, suggesting a sharing of these mediators in cerebral and pulmonary metastases. In contrast, ST6GALNAC5 specifically mediates brain metastasis. Normally restricted to the brain, the expression of ST6GALNAC5 in breast cancer cells enhances their adhesion to brain endothelial cells and their passage through the blood-brain barrier. This co-option of a brain sialyltransferase highlights the role of cell-surface glycosylation in organ-specific metastatic interactions. © 2009 Macmillan Publishers Limited. |
| Keywords: | controlled study; intercellular signaling peptides and proteins; human cell; major clinical study; nonhuman; brain neoplasms; genetic analysis; mouse; animals; mice; gene; breast cancer; gene expression; gene expression profiling; cell infiltration; epidermal growth factor receptor; animal experiment; animal model; receptor, epidermal growth factor; enzyme activity; cell line, tumor; breast neoplasms; cetuximab; capillary; lung metastasis; gene expression regulation, neoplastic; blood; brain; cyclooxygenase 2; nucleotide sequence; cancer cell; blood brain barrier; blood-brain barrier; sialyltransferase; bone; ligand; molecular analysis; brain metastasis; cell isolation; glycosylation; lung; neoplasm metastasis; organ specificity; sialyltransferases |
| Journal Title: | Nature |
| Volume: | 459 |
| Issue: | 7249 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2009-06-18 |
| Start Page: | 1005 |
| End Page: | 1009 |
| Language: | English |
| DOI: | 10.1038/nature08021 |
| PUBMED: | 19421193 |
| PROVIDER: | scopus |
| PMCID: | PMC2698953 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 36" - "Export Date: 30 November 2010" - "CODEN: NATUA" - "Source: Scopus" |
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