TrkA overexpression enhances growth and metastasis of breast cancer cells

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 stablyov erexpress 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 byTrkA 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 immunode efficient 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. Oncogene ( 2009) 28, 1960-1970; doi:10.1038/onc.2009.61; published online 30 March 2009