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         headline:Genes that mediate breast cancer metastasis to the brain
         description:Little is known about the mechanisms by which breast cancer cells metastasize to the brain. Bos et al. now identify three genes that are involved in this process. COX2 and HBEGF have previously been shown to also mediate breast cancer metastasis to the lung, suggesting common biological processes that regulate dissemination to these two organs. In addition, they find that ST6GALNAC5 is specifically involved in brain metastasis, by increasing the adhesion of breast cancer cells to the brain endothelium and migration through the blood–brain barrier. Little is known about the mechanisms by which breast cancer cells metastasize to the brain. By performing gene expression analysis on cells that preferentially infiltrate the brain it has now been possible to identify three genes that are involved in this process, two of which—COX2 and HBEGF—have previously been shown to mediate breast cancer metastasis to the lung. 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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      headline:Genes that mediate breast cancer metastasis to the brain
      description:Little is known about the mechanisms by which breast cancer cells metastasize to the brain. Bos et al. now identify three genes that are involved in this process. COX2 and HBEGF have previously been shown to also mediate breast cancer metastasis to the lung, suggesting common biological processes that regulate dissemination to these two organs. In addition, they find that ST6GALNAC5 is specifically involved in brain metastasis, by increasing the adhesion of breast cancer cells to the brain endothelium and migration through the blood–brain barrier. Little is known about the mechanisms by which breast cancer cells metastasize to the brain. By performing gene expression analysis on cells that preferentially infiltrate the brain it has now been possible to identify three genes that are involved in this process, two of which—COX2 and HBEGF—have previously been shown to mediate breast cancer metastasis to the lung. 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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            name: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
            address:
               name: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA ,
               type:PostalAddress
            type:Organization
      name:Roger R. Gomis
      affiliation:
            name: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
            address:
               name: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA ,
               type:PostalAddress
            type:Organization
            name: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.).
            address:
               name: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.).,
               type:PostalAddress
            type:Organization
      name:Don X. Nguyen
      affiliation:
            name: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
            address:
               name: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA ,
               type:PostalAddress
            type:Organization
      name:Andy J. Minn
      affiliation:
            name:and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, Illinois 60637, USA
            address:
               name:Department of Radiation and Cellular Oncology, and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, Illinois 60637, USA,
               type:PostalAddress
            type:Organization
      name:Marc J. van de Vijver
      affiliation:
            name:Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
            address:
               name:Department of Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands,
               type:PostalAddress
            type:Organization
      name:William L. Gerald
      affiliation:
            name:Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
            address:
               name:Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA,
               type:PostalAddress
            type:Organization
      name:John A. Foekens
      affiliation:
            name:Erasmus MC Rotterdam, Josephine Nefkens Institute and Cancer Genomics Centre
            address:
               name:Department of Medical Oncology, Erasmus MC Rotterdam, Josephine Nefkens Institute and Cancer Genomics Centre, Rotterdam, The Netherlands
               type:PostalAddress
            type:Organization
      name:Joan Massagué
      affiliation:
            name: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
            address:
               name: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA ,
               type:PostalAddress
            type:Organization
            name: Howard Hughes Medical Institute, Chevy Chase, Maryland 20185, USA
            address:
               name: Howard Hughes Medical Institute, Chevy Chase, Maryland 20185, USA ,
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA ,
      name: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA ,
      name: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA ,
      name: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.).,
      name: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA ,
      name: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA ,
      name: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.).,
      name: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA ,
      name:Department of Radiation and Cellular Oncology, and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, Illinois 60637, USA,
      name:Department of Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands,
      name:Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA,
      name:Department of Medical Oncology, Erasmus MC Rotterdam, Josephine Nefkens Institute and Cancer Genomics Centre, Rotterdam, The Netherlands
      name: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA ,
      name: Howard Hughes Medical Institute, Chevy Chase, Maryland 20185, USA ,
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