Integrin-dependent response to laminin-511 regulates breast tumor cell invasion and metastasis

Authors

  • Nicole Kusuma,

    1. Metastasis Research Laboratory, Peter MacCallum Cancer Centre, St-Andrews Place, East-Melbourne, Victoria, Australia
    2. Pathology Department, University of Melbourne, Victoria, Australia
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    • N.K. and D.D. contributed equally to this work

  • Delphine Denoyer,

    1. Translational Research Laboratory, Peter MacCallum Cancer Centre, St-Andrews Place, East-Melbourne, Victoria, Australia
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    • N.K. and D.D. contributed equally to this work

  • Johannes A. Eble,

    1. Excellence Cluster Cardio-Pulmonary System, Center for Molecular Medicine, Vascular Matrix Biology, Frankfurt University Hospital, Frankfurt/Main, Germany
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  • Richard P. Redvers,

    1. Metastasis Research Laboratory, Peter MacCallum Cancer Centre, St-Andrews Place, East-Melbourne, Victoria, Australia
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  • Belinda S. Parker,

    1. Metastasis Research Laboratory, Peter MacCallum Cancer Centre, St-Andrews Place, East-Melbourne, Victoria, Australia
    2. Biochemistry Department, University of Melbourne, Victoria, Australia
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  • Rebecca Pelzer,

    1. Metastasis Research Laboratory, Peter MacCallum Cancer Centre, St-Andrews Place, East-Melbourne, Victoria, Australia
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  • Robin L. Anderson,

    1. Metastasis Research Laboratory, Peter MacCallum Cancer Centre, St-Andrews Place, East-Melbourne, Victoria, Australia
    2. Pathology Department, University of Melbourne, Victoria, Australia
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  • Normand Pouliot

    Corresponding author
    1. Metastasis Research Laboratory, Peter MacCallum Cancer Centre, St-Andrews Place, East-Melbourne, Victoria, Australia
    2. Pathology Department, University of Melbourne, Victoria, Australia
    • Peter MacCallum Cancer Centre, Locked Bag #1, A'Beckett Street, Melbourne Victoria 8006, Australia
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    • Tel.: +61-3-9656-1285, Fax: +61-3-9656-1411


Abstract

The basement membrane protein, laminin (LM)-511, is a potent adhesive and migratory substrate for metastatic breast tumor cells in vitro. Its expression correlates with tumor grade and metastatic potential in vivo. These observations suggest that responsiveness to autocrine or paracrine-derived LM-511 may be an important property regulating breast cancer metastasis in vivo. To address this, we compared the metastatic potential of 4T1 mammary carcinoma cells to that of 4T1 variants isolated by repeated chemotactic migration toward LM-511 in vitro (4T1LMF4) followed by serial injection into the mammary gland and recovery of spontaneous metastases from bone (4T1BM2). Variant subpopulations exhibited a distinct morphology on LM-511 and increased expression of β1 and β4 integrins compared to parental 4T1 cells. Importantly, mice inoculated with 4T1LMF4 and 4T1BM2 variants showed a 2.5- to 4-fold increase in the incidence of spontaneous metastasis to bone compared to 4T1 tumor-bearing mice. Functionally, 4T1BM2 variants were more adherent and more invasive toward LM-511 than parental 4T1 cells. Treatment of 4T1BM2 cells with lebein-1, a disintegrin with selectivity toward LM-type integrin receptors, potently inhibited their migration and invasion toward LM-511. Similarly, α3β1 integrin-dependent migration and invasion of human MDA-MB-231 breast carcinoma cells toward LM-511 were significantly inhibited by lebein-1. Taken together, these results provide strong evidence that LM-511 contributes to the metastasis of breast tumors and suggest that targeting integrin-LM-511 interactions with lebein-1 or other inhibitors of LM-511 receptors may have therapeutic potential for patients with advanced breast cancer.

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