A genetic variant of Aurora kinase A promotes genomic instability leading to highly malignant skin tumors

Enrique C. Torchia, Yiyun Chen, Hong Sheng, Hiroshi Katayama, James Fitzpatrick, William R. Brinkley, Carlos Caulin, Subrata Sen, Dennis R. Roop

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)7207-7215
Number of pages9
JournalCancer Research
Volume69
Issue number18
DOIs
Publication statusPublished - Oct 13 2009
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Torchia, E. C., Chen, Y., Sheng, H., Katayama, H., Fitzpatrick, J., Brinkley, W. R., Caulin, C., Sen, S., & Roop, D. R. (2009). A genetic variant of Aurora kinase A promotes genomic instability leading to highly malignant skin tumors. Cancer Research, 69(18), 7207-7215. https://doi.org/10.1158/0008-5472.CAN-09-1059