Article

Clinical & Experimental Metastasis

, Volume 21, Issue 2, pp 119-128

First online:

A small molecule antagonist of the α v β3 integrin suppresses MDA-MB-435 skeletal metastasis

  • John F. HarmsAffiliated withJake Gittlen Cancer Research Institute, The Pennsylvania State University College of Medicine
  • , Danny R. WelchAffiliated withJake Gittlen Cancer Research Institute, The Pennsylvania State University College of MedicineDepartment of Pathology, University of Alabama at BirminghamComprehensive Cancer Center, University of Alabama at BirminghamCenter for Metabolic Bone Disease, University of Alabama at BirminghamNational Foundation for Cancer Research - Center for Metastasis Research Email author 
  • , Rajeev S. SamantAffiliated withJake Gittlen Cancer Research Institute, The Pennsylvania State University College of MedicineDepartment of Pathology, University of Alabama at BirminghamComprehensive Cancer Center, University of Alabama at Birmingham
  • , Lalita A. ShevdeAffiliated withJake Gittlen Cancer Research Institute, The Pennsylvania State University College of MedicineDepartment of Pathology, University of Alabama at BirminghamComprehensive Cancer Center, University of Alabama at Birmingham
  • , Mary E. MieleAffiliated withDepartment of Medical Technology, University of Delaware
  • , Geetha R. BabuAffiliated withJake Gittlen Cancer Research Institute, The Pennsylvania State University College of Medicine
  • , Steven F. GoldbergAffiliated withJake Gittlen Cancer Research Institute, The Pennsylvania State University College of Medicine
  • , Virginia R. GilmanAffiliated withDepartment of Biochemistry & MOlecular Biology, Penn State University
  • , Donna M. SosnowskiAffiliated withDepartment of Biochemistry & MOlecular Biology, Penn State University
    • , Dianalee A. CampoAffiliated withDepartment of Biochemistry & MOlecular Biology, Penn State University
    • , Carol V. GayAffiliated withNational Foundation for Cancer Research - Center for Metastasis ResearchDepartment of Biochemistry & MOlecular Biology, Penn State University
    • , Lynn R. BudgeonAffiliated withJake Gittlen Cancer Research Institute, The Pennsylvania State University College of Medicine
    • , Robin MercerAffiliated withDepartment of Biochemistry & MOlecular Biology, Penn State University
    • , Jennifer JewellAffiliated withDepartment of Biochemistry & MOlecular Biology, Penn State University
    • , Andrea M. MastroAffiliated withNational Foundation for Cancer Research - Center for Metastasis ResearchDepartment of Biochemistry & MOlecular Biology, Penn State University
    • , Henry J. DonahueAffiliated withNational Foundation for Cancer Research - Center for Metastasis ResearchDepartment of Orthopaedics & Rehabilitation, Pennsylvania State University College of Medicine
    • , Nuray ErinAffiliated withJake Gittlen Cancer Research Institute, The Pennsylvania State University College of Medicine
    • , Michael T. DebiesAffiliated withJake Gittlen Cancer Research Institute, The Pennsylvania State University College of Medicine
    • , William J. MeehanAffiliated withJake Gittlen Cancer Research Institute, The Pennsylvania State University College of Medicine
    • , Amy L. JonesAffiliated withDiscovery Oncology Pharmacology & Analytical Sciences Center, Pfizer Corporation
    • , Gabriel MbalavieleAffiliated withDiscovery Oncology Pharmacology & Analytical Sciences Center, Pfizer Corporation
    • , Allen NickolsAffiliated withDiscovery Oncology Pharmacology & Analytical Sciences Center, Pfizer Corporation
    • , Neil D. ChristensenAffiliated withJake Gittlen Cancer Research Institute, The Pennsylvania State University College of Medicine
    • , Robert MellyAffiliated withJake Gittlen Cancer Research Institute, The Pennsylvania State University College of Medicine
    • , Lisa N. BeckAffiliated withJake Gittlen Cancer Research Institute, The Pennsylvania State University College of Medicine
    • , Julia KentAffiliated withJake Gittlen Cancer Research Institute, The Pennsylvania State University College of Medicine
    • , Randall K. RaderAffiliated withDepartment of Orthopaedics & Rehabilitation, Pennsylvania State University College of Medicine
    • , John J. KotykAffiliated withDiscovery Oncology Pharmacology & Analytical Sciences Center, Pfizer Corporation
    • , M.D. PagelAffiliated withDiscovery Oncology Pharmacology & Analytical Sciences Center, Pfizer Corporation
    • , William F. WestlinAffiliated withDiscovery Oncology Pharmacology & Analytical Sciences Center, Pfizer Corporation
    • , David W. GriggsAffiliated withDiscovery Oncology Pharmacology & Analytical Sciences Center, Pfizer Corporation

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Abstract

Introduction: Breast cancer is one of the most common malignancies affecting women in the United States and Europe. Approximately three out of every four women with breast cancer develop metastases in bone which, in turn, diminishes quality of life. The αvβ3 integrin has previously been implicated in multiple aspects of tumor progression, metastasis and osteoclast bone resorption. Therefore, we hypothesized that the αvβ3-selective inhibitor, S247, would decrease the development of osteolytic breast cancer metastases. Materials and methods: Cells were treated in vitro with S247 and assessed for viability and adhesion to matrix components. Athymic mice received intracardiac (left ventricle) injections of human MDA-MB-435 breast carcinoma cells expressing enhanced green-fluorescent protein. Mice were treated with vehicle (saline) or S247 (1, 10, or 100 mg/kg/d) using osmotic pumps beginning either one week before or one week after tumor cell inoculation. Bones were removed and examined by fluorescence microscopy and histology. The location and size of metastases were recorded. Results and conclusions: IC50 for S247 adhesion to αvβ3 or αIIBβ3a substrates was 0.2 nM vs. 244 nM, respectively. Likewise, S247 was not toxic at doses up to 1000 μM. However, osteoclast cultures treated with S247 exhibited marked morphological changes and impaired formation of the actin sealing zone. When S247 was administered prior to tumor cells, there was a significant, dose-dependent reduction (25–50% of vehicle-only-treated mice; P=0.002) in osseous metastasis. Mice receiving S247 after tumor cell inoculation also developed fewer bone metastases, but the difference was not statistically significant. These data suggest that, in the MDA-MB-435 model, the αvβ3 integrin plays an important role in early events (e.g., arrest of tumor cells) in bone metastasis. Furthermore, the data suggest that αvβ3 inhibitors may be useful in the treatment and/or prevention of breast cancer metastases in bone.

breast cancer metastasis bone MDA-MB-435 green fluorescent protein