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

被引：0
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作者：
D Zhang
T Shimizu
N Araki
T Hirota
M Yoshie
K Ogawa
N Nakagata
M Takeya
H Saya
机构：
[1] Graduate School of Medical Sciences,Department of Tumor Genetics and Biology
[2] Kumamoto University,Department of Experimental Pathology
[3] Cancer Institute of Japanese Foundation for Cancer Research,Department of Pathology
[4] Asahikawa Medical College,Division of Reproductive Engineering
[5] Center for Animal Resources and Development,Department of Cell Pathology
[6] Kumamoto University,undefined
[7] Graduate School of Medical Sciences,undefined
[8] Kumamoto University,undefined
[9] 6Current address: Breast Cancer Translational Research Laboratory,undefined
[10] Department of Stem Cell Transplantation and Cellular Therapy,undefined
[11] The University of Texas MD Anderson Cancer Center,undefined
[12] Houston,undefined
[13] TX,undefined
[14] USA.,undefined
[15] 7Current address: Division of Gene Regulation,undefined
[16] Institute for Advanced Medical Research,undefined
[17] Keio University School of Medicine,undefined
[18] Tokyo,undefined
[19] Japan.,undefined
来源：
Oncogene | 2008年 / 27卷
关键词：
Aurora A; polyploidy; apoptosis; senescence; p16; DNA damage;
D O I：
暂无
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摘要：
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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页码：4305 / 4314
页数：9
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