The mitotic kinase Aurora--a promotes distant metastases by inducing epithelial-to-mesenchymal transition in ERα(+) breast cancer cells.
The mitotic kinase Aurora--a promotes distant metastases by inducing epithelial-to-mesenchymal transition in ERα(+) breast cancer cells.
复制标题
作者：
在这项研究中，我们证明了Raf-1致癌信号的组成性激活诱导Aurora-A有丝分裂激酶的稳定和积累，最终驱动雌激素受体α阳性（ERα+）乳腺癌细胞从上皮向高度侵袭性间充质表型的转变。从上皮样表型向间充质样表型的转变的特征是ERα表达减少、HER-2/Neu过表达和CD 24表面受体（CD 24-/low）丢失。重要的是，关键的上皮-间质转化（EMT）标志物的表达和干细胞基因SOX 2的上调与获得干细胞样特性有关，例如体外形成乳腺球和体内肿瘤自我更新的能力。此外，异常的Aurora-A激酶活性诱导SMAD 5的磷酸化和核转位，表明Aurora-A和SMAD 5信号通路在EMT、干性和最终肿瘤进展的发展中的新型相互作用。重要的是，Aurora-A激酶活性的药理学和分子抑制恢复了与ERα表达、HER-2/Neu下调、EMT抑制和自我更新能力受损相关的CD 24+上皮表型，从而抑制了远处转移。总之，我们的研究结果首次显示Aurora-A激酶在EMT通路激活中的因果作用，EMT通路负责ERα+乳腺癌细胞中远处转移的发展。此外，这项研究具有重要的翻译意义，因为它突出了有丝分裂激酶Aurora-A作为一种新的有前途的治疗靶点，可以选择性地消除高度侵袭性的癌细胞，提高对传统内分泌治疗耐药的ERα+乳腺癌患者的无病生存率和总生存率。
In this study, we demonstrate that constitutive activation of Raf-1 oncogenic signaling induces stabilization and accumulation of Aurora-A mitotic kinase that ultimately drives the transition from an epithelial to a highly invasive mesenchymal phenotype in estrogen receptor α-positive (ERα+) breast cancer cells. The transition from an epithelial- to a mesenchymal-like phenotype was characterized by reduced expression of ERα, HER-2/Neu overexpression and loss of CD24 surface receptor (CD24 –/low). Importantly, expression of key epithelial-to-mesenchymal transition (EMT) markers and upregulation of the stemness gene SOX2 was linked to acquisition of stem cell-like properties such as the ability to form mammospheres in vitro and tumor self-renewal in vivo. Moreover, aberrant Aurora-A kinase activity induced phosphorylation and nuclear translocation of SMAD5, indicating a novel interplay between Aurora-A and SMAD5 signaling pathways in the development of EMT, stemness and ultimately tumor progression. Importantly, pharmacological and molecular inhibition of Aurora-A kinase activity restored a CD24+ epithelial phenotype that was coupled to ERα expression, downregulation of HER-2/Neu, inhibition of EMT and impaired self-renewal ability, resulting in the suppression of distant metastases. Taken together, our findings show for the first time the causal role of Aurora-A kinase in the activation of EMT pathway responsible for the development of distant metastases in ERα+ breast cancer cells. Moreover, this study has important translational implications because it highlights the mitotic kinase Aurora-A as a novel promising therapeutic target to selectively eliminate highly invasive cancer cells and improve the disease-free and overall survival of ERα+ breast cancer patients resistant to conventional endocrine therapy.