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Romagnoli, Mathilde; Mineva, Nora D; Polmear, Michael; Conrad, Catharina; Srinivasan, Srimathi; Loussouarn, Delphine; Barillé‐Nion, Sophie; Georgakoudi, Irene; Dagg, Áine; McDermott, Enda W; Duffy, Michael J; McGowan, Patricia M.; Schlomann, Uwe; Parsons, Maddy; Bartsch, Jörg W; Sonenshein, Gail E

ADAM8 expression in invasive breast cancer promotes tumor dissemination and metastasis

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  • Medientyp: E-Artikel
  • Titel: ADAM8 expression in invasive breast cancer promotes tumor dissemination and metastasis
  • Beteiligte: Romagnoli, Mathilde; Mineva, Nora D; Polmear, Michael; Conrad, Catharina; Srinivasan, Srimathi; Loussouarn, Delphine; Barillé‐Nion, Sophie; Georgakoudi, Irene; Dagg, Áine; McDermott, Enda W; Duffy, Michael J; McGowan, Patricia M.; Schlomann, Uwe; Parsons, Maddy; Bartsch, Jörg W; Sonenshein, Gail E
  • Erschienen: Springer Science and Business Media LLC, 2014
  • Erschienen in: EMBO Molecular Medicine
  • Sprache: Englisch
  • DOI: 10.1002/emmm.201303373
  • ISSN: 1757-4676; 1757-4684
  • Schlagwörter: Molecular Medicine
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>The transmembrane metalloprotease‐disintegrin <jats:styled-content style="fixed-case">ADAM</jats:styled-content>8 mediates cell adhesion and shedding of ligands, receptors and extracellular matrix components. Here, we report that <jats:styled-content style="fixed-case">ADAM</jats:styled-content>8 is abundantly expressed in breast tumors and derived metastases compared to normal tissue, especially in triple‐negative breast cancers (<jats:styled-content style="fixed-case">TNBC</jats:styled-content>s). Furthermore, high <jats:italic><jats:styled-content style="fixed-case">ADAM</jats:styled-content>8</jats:italic> levels predicted poor patient outcome. Consistently, <jats:styled-content style="fixed-case">ADAM</jats:styled-content>8 promoted an aggressive phenotype of <jats:styled-content style="fixed-case">TNBC</jats:styled-content> cells in culture. In a mouse orthotopic model, tumors derived from <jats:styled-content style="fixed-case">TNBC</jats:styled-content> cells with <jats:styled-content style="fixed-case">ADAM</jats:styled-content>8 knockdown failed to grow beyond a palpable size and displayed poor vascularization. Circulating tumor cells and brain metastases were also significantly reduced. Mechanistically, <jats:styled-content style="fixed-case">ADAM</jats:styled-content>8 stimulated both angiogenesis through release of <jats:styled-content style="fixed-case">VEGF</jats:styled-content>‐A and transendothelial cell migration via β1‐integrin activation. <jats:italic>In vivo</jats:italic>, treatment with an anti‐<jats:styled-content style="fixed-case">ADAM</jats:styled-content>8 antibody from the time of cell inoculation reduced primary tumor burden and metastases. Furthermore, antibody treatment of established tumors profoundly decreased metastases in a resection model. As a non‐essential protein under physiological conditions, <jats:styled-content style="fixed-case">ADAM</jats:styled-content>8 represents a promising novel target for treatment of <jats:styled-content style="fixed-case">TNBC</jats:styled-content>s, which currently lack targeted therapies and frequently progress with fatal dissemination.</jats:p>
  • Zugangsstatus: Freier Zugang