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TrkA overexpression enhances growth and metastasis of breast cancer cells

机译：TrkA过表达促进乳腺癌细胞的生长和转移

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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.
机译：神经营养蛋白酪氨酸激酶受体的Trk家族正在成为非神经组织致癌进展中的重要角色。在这里，我们显示出与正常乳腺组织相比，乳腺肿瘤呈现高水平的TrkA和磷酸化TrkA。为了进一步评估TrkA过表达在乳腺癌发展中的确切功能，我们使用稳定过表达TrkA的乳腺癌细胞进行了一系列生物学测试。我们证明（1）TrkA的过量表达促进体外细胞生长，迁移和侵袭; （2）TrkA的过表达本身赋予其酪氨酸激酶活性的组成型激活; （3）TrkA过表达激活包括PI3K-Akt和ERK / p38 MAP激酶在内的信号通路，是维持更具攻击性的细胞表型所必需的; （4）TrkA的过表达增强了免疫缺陷小鼠中异种移植乳腺癌细胞的肿瘤生长，血管生成和转移。此外，从肺中回收的转移细胞显示出增强的厌食药抗性，这被药理学抑制剂K252a所消除，这表明TrkA促进的乳腺肿瘤转移可以至少部分地通过增强厌食药抗性来介导。总之，这些结果提供了第一个直接证据，表明TrkA的过表达增强了乳腺癌细胞的致瘤特性，并指出TrkA作为乳腺癌治疗的潜在靶标。

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