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Integrin activation controls metastasis in human breast cancer

Academic Article
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Overview

authors

  • Felding, Brunhilde
  • O'Toole, T. E.
  • Smith, J. W.
  • Fransvea, E.
  • Ruggeri, Zaverio
  • Ginsberg, Mark
  • Hughes, P. E.
  • Pampori, N.
  • Shattil, S. J.
  • Saven, A.
  • Mueller, B. M.

publication date

  • February 2001

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • Metastasis is the primary cause of death in human breast cancer. Metastasis to bone, lungs, liver, and brain involves dissemination of breast cancer cells via the bloodstream and requires adhesion within the vasculature. Blood cell adhesion within the vasculature depends on integrins, a family of transmembrane adhesion receptors, and is regulated by integrin activation. Here we show that integrin alpha v beta 3 supports breast cancer cell attachment under blood flow conditions in an activation-dependent manner. Integrin alpha v beta 3 was found in two distinct functional states in human breast cancer cells. The activated, but not the nonactivated, state supported tumor cell arrest during blood flow through interaction with platelets. Importantly, activated alpha v beta 3 was expressed by freshly isolated metastatic human breast cancer cells and variants of the MDA-MB 435 human breast cancer cell line, derived from mammary fat pad tumors or distant metastases in severe combined immunodeficient mice. Expression of constitutively activated mutant alpha v beta 3(D723R), but not alpha v beta 3(WT), in MDA-MB 435 cells strongly promoted metastasis in the mouse model. Thus breast cancer cells can exhibit a platelet-interactive and metastatic phenotype that is controlled by the activation of integrin alpha v beta 3. Consequently, alterations within tumors that lead to the aberrant control of integrin activation are expected to adversely affect the course of human breast cancer.

subject areas

  • Animals
  • Blood Platelets
  • Breast Neoplasms
  • Cell Division
  • Cell Movement
  • Female
  • Humans
  • Ligands
  • Mice
  • Mice, SCID
  • Neoplasm Metastasis
  • Phenotype
  • Receptors, Vitronectin
  • Tumor Cells, Cultured
  • Vitronectin
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Identity

PubMed Central ID

  • PMC29346

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.98.4.1853

PubMed ID

  • 11172040
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Additional Document Info

start page

  • 1853

end page

  • 1858

volume

  • 98

issue

  • 4

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