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, Wilma L 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 journalArticle

65 Scopus citations

Abstract

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
JournalOncogene
Volume33
Issue number5
DOIs
StatePublished - Jan 30 2014

Keywords

  • Breast Cancer
  • Metastases
  • Stemness

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    D'Assoro, A. B., Liu, T., Quatraro, C., Amato, A., Opyrchal, M., Leontovich, A., Ikeda, Y., Ohmine, S., Lingle, W. L., Suman, V., Ecsedy, J., Iankov, I., Di Leonardo, A., Ayers-Inglers, J., Degnim, A., Billadeau, D., McCubrey, J., Ingle, J., Salisbury, J. L., & Galanis, E. (2014). The mitotic kinase aurora-A promotes distant metastases by inducing epithelial-to-mesenchymal transition in ER + breast cancer cells. Oncogene, 33(5), 599-610. https://doi.org/10.1038/onc.2012.628