Genes that mediate breast cancer metastasis to the brain

Paula D. Bos1, Xiang H.-F. Zhang1, Cristina Nadal1,7, Weiping Shu1, Roger R. Gomis1,7, Don X. Nguyen1, Andy J. Minn2, Marc J. van de Vijver3, William L. Gerald4, John A. Foekens5 & Joan Massagué1,6

Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
Department of Radiation and Cellular Oncology, and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, Illinois 60637, USA
Department of Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
Department of Medical Oncology, Erasmus MC Rotterdam, Josephine Nefkens Institute and Cancer Genomics Centre, Rotterdam, The Netherlands
Howard Hughes Medical Institute, Chevy Chase, Maryland 20185, USA
Present addresses: Institut de Malalties Hemato-Oncològiques, Hospital Clínic, 08036 Barcelona, Spain (C.N.); Oncology Programme, Institute for Research in Biomedicine, 08028 Barcelona, Spain (R.R.G.).
Correspondence to: Joan Massagué1,6 Correspondence and requests for materials should be addressed to J.M. (Email: j-massague@ski.mskcc.org).
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 2,6-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.