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

Oncogene volume 33, pages 599–610 (2014)Cite this article

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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 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.

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Acknowledgements

This study was supported by NCI CA72836 to JLS, USAMRMC BC022276 and Intramural RECDA Award to ABD, the Italian Association for Cancer Research (AIRC) to AA, the Mayo Clinic Breast Cancer Specialized Program of Research Excellence NIH CA116201 to JI and the Mayo Clinic School of Medicine. This study was also supported by the Atwater Foundation. We also wish to acknowledge the Cytogenetic Shared Resource and TACMA core facilities of the Mayo Clinic Comprehensive Cancer Center for performing SKY, routine cytogenetic and immunohistochemistry analysis and assisting us with the interpretation of the results.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, USA, MN

    A B D'Assoro, T liu, C Quatraro, A Amato, J Ayers-Inglers & J L Salisbury

  2. Department of Medical Oncology, Mayo Clinic College of Medicine, Rochester, USA, MN

    A B D'Assoro, M Opyrchal, V Suman, D Billadeau, J Ingle & E Galanis

  3. Department of Cellular and Developmental Biology, Palermo, Italy

    A Amato & A Di Leonardo

  4. Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, USA, MN

    M Opyrchal, Y Ikeda, S Ohmine, I Iankov & E Galanis

  5. Department of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, USA, MN

    A Leontovich

  6. Department of Experimental Pathology, Mayo Clinic College of Medicine, Rochester, USA, MN

    W Lingle

  7. Department of Oncology, Millennium Pharmaceuticals Inc., Cambridge, MA, USA

    J Ecsedy

  8. Department of General Surgery, Mayo Clinic College of Medicine, Rochester, USA, MN

    A Degnim

  9. Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA

    J McCubrey

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Correspondence to A B D'Assoro.

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D'Assoro, A., liu, T., Quatraro, C. et al. The mitotic kinase Aurora-A promotes distant metastases by inducing epithelial-to-mesenchymal transition in ERα+ breast cancer cells. Oncogene 33, 599–610 (2014). https://doi.org/10.1038/onc.2012.628

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