The mitotic kinase aurora-A promotes distant metastases by inducing epithelial-to-mesenchymal transition in ER + breast cancer cells

A. B. D'Assoro, T. Liu, C. Quatraro, A. Amato, M. Opyrchal, A. Leontovich, Y. Ikeda, S. Ohmine, W. Lingle, V. Suman, J. Ecsedy, I. Iankov, A. Di Leonardo, J. Ayers-Inglers, A. Degnim, D. Billadeau, J. McCubrey, J. Ingle, J. L. Salisbury, E. Galanis

Research output: Contribution to journalArticlepeer-review

75 Scopus citations


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 positive (ER+) breast cancer cells. The transition from an epithelial- to a mesenchymal-like phenotype was characterized by reduced expression of ER, HER-2/Neu overexpression and loss of CD24 su-rface 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 ER 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 ER+ 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 ER+ breast cancer patients resistant to conventional endocrine therapy.

Original languageEnglish (US)
Pages (from-to)599-610
Number of pages12
Issue number5
StatePublished - Jan 30 2014


  • Breast Cancer
  • Metastases
  • Stemness

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research


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