A genetic variant of Aurora kinase A promotes genomic instability leading to highly malignant skin tumors.
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 metastatic 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.
Torchia
Enrique C
EC
Department of Dermatology, University of Colorado Denver at Anschutz Medical Campus, Aurora, Colorado 80045, USA.
Chen
Yiyun
Y
Sheng
Hong
H
Katayama
Hiroshi
H
Fitzpatrick
James
J
Brinkley
William R
WR
Caulin
Carlos
C
Sen
Subrata
S
Roop
Dennis R
DR
D015127:9,10-Dimethyl-1,2-benzanthracene; D000328:Adult; D000818:Animals; D064096:Aurora Kinase A; D064127:Aurora Kinases; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D016923:Cell Death / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D042822:Genomic Instability; D006801:Humans; D015603:Keratinocytes / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010212:Papilloma / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D008941:Spindle Apparatus / Q000201:enzymology / Q000473:pathology
D015127:9,10-Dimethyl-1,2-benzanthracene; C576917:AURKA protein, human; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases