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Overexpression of aurora kinase A in mouse mammary epithelium induces genetic instability preceding mammary tumor formation

Oncogene volume 25, pages 7148–7158 (2006)Cite this article

Abstract

Aurora-A/STK15/BTAK, which encodes a centrosome-associated kinase, is amplified and overexpressed in multiple types of human tumors, including breast cancer. However, the causal relationship between overexpression of Aurora-A and tumorigenesis has not been fully established due to contradictory data obtained from different experimental systems. To investigate this, we generated a mouse strain that carries an MMTV-Aurora-A transgene. We showed that all the MMTV-Aurora-A mice displayed enhanced branch morphogenesis in the mammary gland and about 40% developed mammary tumors at 20 months of age. The tumor incidence was significantly increased in a p53+/− mutation background with about 70% MMTV-Aurora-A;p53+/− animals developed tumors at 18 months of age. Of note, overexpression of Aurora-A led to genetic instability, characterized by centrosome amplification, chromosome tetraploidization and premature sister chromatid segregation, at stages prior to tumor formation. Most notably, the severe chromosomal abnormality did not cause cell death owing to the activation of AKT pathway, including elevated levels of phosphorylated AKT and mammalian target of rapamycin, and nuclear accumulation of cyclin D1, which enabled continuous proliferation of the tetraploid cells. These data establish Aurora-A as an oncogene that causes malignant transformation through inducing genetic instability and activating oncogenic pathways such as AKT and its downstream signaling.

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Acknowledgements

We thank members of Deng laboratory for critically reading this manuscript and discussion of this project. This research was supported by the Intramural Research Program of the National Institutes of Diabetes and Digestive and Kidney Diseases, NIH, USA.

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Authors and Affiliations

  1. Genetics of Development and Disease Branch, NIDDK, NIH, Bethesda, MD, USA

    X Wang, Y-X Zhou, W Qiao, Y Tominaga & C-X Deng

  2. The Derald H Ruttenberg Cancer Center, The Mount Sinai School of Medicine, New York University, New York, NY, USA

    M Ouchi & T Ouchi

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  1. X Wang
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  2. Y-X Zhou
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  3. W Qiao
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Correspondence to C-X Deng.

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Wang, X., Zhou, YX., Qiao, W. et al. Overexpression of aurora kinase A in mouse mammary epithelium induces genetic instability preceding mammary tumor formation. Oncogene 25, 7148–7158 (2006). https://doi.org/10.1038/sj.onc.1209707

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