1. ¹Genetics of Development and Disease Branch, NIDDK, NIH, Bethesda, MD, USA
2. ²The Derald H Ruttenberg Cancer Center, The Mount Sinai School of Medicine, New York University, New York, NY, USA

Correspondence: Dr C-X Deng, Genetics of Development and Disease Branch, NIDDK, NIH, 10/9N105, 10 Center Drive, Bethesda, MD 20892, USA. E-mail: chuxiad@bdg10.niddk.nih.gov

Received 30 November 2005; Revised 30 March 2006; Accepted 17 April 2006; Published online 22 May 2006.

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.