Genes that mediate breast cancer metastasis to the brain

Abstract

The molecular basis for breast cancer metastasis to the brain is largely unknown1,2. Brain relapse typically occurs years after the removal of a breast tumour2,3,4, 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 liver5,6, suggesting a sharing of these mediators in cerebral and pulmonary metastases. In contrast, ST6GALNAC5 specifically mediates brain metastasis. Normally restricted to the brain7, 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.

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Figure 1: Isolation and characterization of brain metastatic variants.
Figure 2: COX2 and EGFR ligands as mediators of brain metastasis and BBB transmigration.
Figure 3: ST6GALNAC5 expression and activity in brain metastasis from breast cancer.
Figure 4: The brain-specific sialyltransferase ST6GALNAC5 as a BBB extravasation and brain metastasis gene.

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

The clinical microarray data on the brain metastatic cell lines have been deposited in NCBI’s Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo) under the GEO series accession number GSE12237.

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Acknowledgements

This work is dedicated to the memory of our colleague W. Gerald. We thank E. Eugenin, E. Brogi, M. Drobnjac, K. LaPerle, M. Smid, A. Viale and K. Manova-Todorova for advice and support. We thank L. DeAngelis, A. Lassman, E. Holland, J. Posner and members of the Massagué laboratory for discussions. This work was supported by grants from the National Institutes of Health (U54 CA126518), the Kleberg Foundation and the Hearst Foundation, and the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO). J.M. is an investigator of the Howard Hughes Medical Institute.

Author Contributions P.D.B. and J.M. designed experiments, analysed data and wrote the manuscript. J.M. supervised the research. X.H.-F.Z. performed bioinformatics analyses. P.D.B. performed experiments. W.S. assisted with experiments. C.N. and R.R.G. isolated metastatic cells from clinical samples. D.X.N. helped with gliosis immunostaining and confocal microscopy. A.J.M. identified LMS clinical correlation with brain relapse. W.L.G., J.A.F. and M.J.V.d.V. obtained, classified and processed breast tumour samples. All authors discussed the results and commented on the manuscript.

Author information

Correspondence to Joan Massagué.

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Supplementary Information

This file contains Supplementary Tables 1-7 and Supplementary Figures 1-12 with Legends. (PDF 13588 kb)

Supplementary Table

This file contains Supplementary Table 8. Supplementary Table 8 was added on 3 June 2009. (PDF 89 kb)

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