Abstract
Aurora A mitotic kinase is frequently overexpressed in various human cancers and is widely considered to be an oncoprotein. However, the cellular contexts in which Aurora A induces malignancy in vivo are still unclear. We previously reported a mouse model in which overexpression of human Aurora A in the mammary gland leads to small hyperplastic changes but not malignancy because of the induction of p53-dependent apoptosis. To study the additional factors required for Aurora A-associated tumorigenesis, we generated a new Aurora A overexpression mouse model that lacks p53. We present evidence here that Aurora A overexpression in primary mouse embryonic fibroblasts (MEFs) that lack p53 overrides postmitotic checkpoint and leads to the formation of multinucleated polyploid cells. Induction of Aurora A overexpression in the mammary glands of p53-deficient mice resulted in development of precancerous lesions that were histologically similar to atypical ductal hyperplasia in human mammary tissue and showed increased cellular senescence and p16 expression. We further observed DNA damage in p53-deficient primary MEFs after Aurora A overexpression. Our results suggest that Aurora A overexpression in mammary glands is insufficient for the development of malignant tumors in p53-deficient mice because of the induction of cellular senescence. Both p53 and p16 are critical in preventing mammary gland tumorigenesis in the Aurora A overexpression mouse model.
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Acknowledgements
We thank Dr Kimi Araki (Kumamoto University) for providing pCAG-CAT-lacZ plasmid; Mr Takenobu Nakagawa (Kumamoto University) for technical assistance; Dr Izumu Saito and Dr Yumi Kanegae (University of Tokyo) for providing adenoviral luciferase, AxCANCre and p16-expressing adenovirus; Mrs Christine F Wogan (The University of Texas MD Anderson Cancer Center) and Dr Sampetrean Oltea (Kumamoto University) for editorial assistance; members of the Saya laboratory for valuable suggestions and members of the Gene Technology Center at Kumamoto University for their technical assistance. This work was supported by a grant for Cancer Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to HS).
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Zhang, D., Shimizu, T., Araki, N. et al. Aurora A overexpression induces cellular senescence in mammary gland hyperplastic tumors developed in p53-deficient mice. Oncogene 27, 4305–4314 (2008). https://doi.org/10.1038/onc.2008.76
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DOI: https://doi.org/10.1038/onc.2008.76
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