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Aurora A overexpression induces cellular senescence in mammary gland hyperplastic tumors developed in p53-deficient mice

Oncogene volume 27, pages 4305–4314 (2008)Cite this article

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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Author notes

  1. D Zhang

    Present address: 6Current address: Breast Cancer Translational Research Laboratory, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,

  2. T Shimizu & H Saya

    Present address: 7Current address: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.,

Authors and Affiliations

  1. Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

    D Zhang, T Shimizu, N Araki & H Saya

  2. Department of Experimental Pathology, Cancer Institute of Japanese Foundation for Cancer Research, Tokyo, Japan

    T Hirota

  3. Department of Pathology, Asahikawa Medical College, Asahikawa, Japan

    M Yoshie & K Ogawa

  4. Division of Reproductive Engineering, Center for Animal Resources and Development, Kumamoto University, Kumamoto, Japan

    N Nakagata

  5. Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

    M Takeya

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Correspondence to H Saya.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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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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