TrkA overexpression enhances growth and metastasis of breast cancer cells

Oncogene. 2009 May 7;28(18):1960-70. doi: 10.1038/onc.2009.61. Epub 2009 Mar 30.


The Trk family of neurotrophin tyrosine kinase receptors is emerging as an important player in carcinogenic progression in non-neuronal tissues. Here, we show that breast tumors present high levels of TrkA and phospho-TrkA compared to normal breast tissues. To further evaluate the precise functions of TrkA overexpression in breast cancer development, we have performed a series of biological tests using breast cancer cells that stably overexpress TrkA. We show that (1) TrkA overexpression promoted cell growth, migration and invasion in vitro; (2) overexpression of TrkA per se conferred constitutive activation of its tyrosine kinase activity; (3) signal pathways including PI3K-Akt and ERK/p38 MAP kinases were activated by TrkA overexpression and were required for the maintenance of a more aggressive cellular phenotype; and (4) TrkA overexpression enhanced tumor growth, angiogenesis and metastasis of xenografted breast cancer cells in immunodeficient mice. Moreover, recovered metastatic cells from the lungs exhibited enhanced anoikis resistance that was abolished by the pharmacological inhibitor K252a, suggesting that TrkA-promoted breast tumor metastasis could be mediated at least in part by enhancing anoikis resistance. Together, these results provide the first direct evidence that TrkA overexpression enhances the tumorigenic properties of breast cancer cells and point to TrkA as a potential target in breast cancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anoikis / physiology
  • Biopsy
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Breast Neoplasms / surgery
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation*
  • Extracellular Signal-Regulated MAP Kinases / physiology
  • Female
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Mice
  • Mice, SCID
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neovascularization, Pathologic
  • Phosphatidylinositol 3-Kinases / physiology
  • Proto-Oncogene Proteins c-akt / physiology
  • RNA, Messenger / metabolism
  • Receptor, trkA / genetics*
  • Signal Transduction / physiology
  • Xenograft Model Antitumor Assays / methods
  • p38 Mitogen-Activated Protein Kinases / physiology


  • RNA, Messenger
  • Green Fluorescent Proteins
  • Phosphatidylinositol 3-Kinases
  • Receptor, trkA
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases