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A Genetic Variant of Aurora Kinase A Promotes Genomic Instability Leading to Highly Malignant Skin Tumors

¹ Department of Dermatology and ² Regenerative Medicine and Stem Cell Biology Program, University of Colorado Denver at Anschutz Medical Campus, Aurora, Colorado and ³ Department of Molecular and Cellular Biology, Baylor College of Medicine; Departments of ⁴ Molecular Pathology and ⁵ Head and Neck Surgery, the University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Dennis R. Roop, Department of Dermatology, University of Colorado, P.O. Box 6511, Aurora, CO 80045. Phone: 303-724-3050; Fax: 303-724-3051; E-mail: Dennis.Roop{at}UCDenver.edu.

Key Words: Aurora-A • genomic instability • SCC • tumorigenesis

Aurora kinase A (Aurora-A) belongs to a highly conserved family of mitotis-regulating serine/threonine kinases implicated in epithelial cancers. Initially we examined Aurora-A expression levels at different stages of human skin cancer. Nuclear Aurora-A was detected in benign lesions and became more diffused but broadly expressed in well and poorly differentiated squamous cell carcinomas (SCC), indicating that Aurora-A deregulation may contribute to SCC development. To mimic the overexpression of Aurora-A observed in human skin cancers, we established a gene-switch mouse model in which the human variant of Aurora-A (Phe31Ile) was expressed in the epidermis upon topical application of the inducer RU486 (Aurora-AGS). Overexpression of Aurora-A alone or in combination with the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA), did not result in SCC formation in Aurora-AGS mice. Moreover, Aurora-A overexpression in naive keratinocytes resulted in spindle defects in vitro and marked cell death in vivo, suggesting that the failure of Aurora-A to initiate tumorigenesis was due to induction of catastrophic cell death. However, Aurora-A overexpression combined with exposure to TPA and the mutagen 7,12-dimethylbenz(a)anthracene accelerated SCC development with greater metastastic activity than control mice, indicating that Aurora-A cannot initiate skin carcinogenesis but rather promotes the malignant conversion of skin papillomas. Further characterization of SCCs revealed centrosome amplification and genomic alterations by array CGH analysis, indicating that Aurora-A overexpression induces a high level of genomic instability that favors the development of aggressive and metastatic tumors. Our findings strongly implicate Aurora-A overexpression in the malignant progression of skin tumors and suggest that Aurora-A may be an important therapeutic target. [Cancer Res 2009;69(18):7207–15]