Overexpression of aurora kinase A in mouse mammary epithelium induces genetic instability preceding mammary tumor formation.
Aurora-A/STK15/BTAK, which encodes a centrosome-associated kinase, is amplified and overexpressed in multiple types of human tumors, including breast cancer. However, the causal relationship between overexpression of Aurora-A and tumorigenesis has not been fully established due to contradictory data obtained from different experimental systems. To investigate this, we generated a mouse strain that carries an MMTV-Aurora-A transgene. We showed that all the MMTV-Aurora-A mice displayed enhanced branch morphogenesis in the mammary gland and about 40% developed mammary tumors at 20 months of age. The tumor incidence was significantly increased in a p53(+/-) mutation background with about 70% MMTV-Aurora-A;p53(+/-) animals developed tumors at 18 months of age. Of note, overexpression of Aurora-A led to genetic instability, characterized by centrosome amplification, chromosome tetraploidization and premature sister chromatid segregation, at stages prior to tumor formation. Most notably, the severe chromosomal abnormality did not cause cell death owing to the activation of AKT pathway, including elevated levels of phosphorylated AKT and mammalian target of rapamycin, and nuclear accumulation of cyclin D1, which enabled continuous proliferation of the tetraploid cells. These data establish Aurora-A as an oncogene that causes malignant transformation through inducing genetic instability and activating oncogenic pathways such as AKT and its downstream signaling.
Wang
X
X
Genetics of Development and Disease Branch, NIDDK, NIH, Bethesda, MD 20892, USA.
Zhou
Y-X
YX
Qiao
W
W
Tominaga
Y
Y
Ouchi
M
M
Ouchi
T
T
Deng
C-X
CX
D000818:Animals; D064096:Aurora Kinase A; D064127:Aurora Kinases; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002869:Chromosome Aberrations; D004848:Epithelium / Q000201:enzymology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008321:Mammary Glands, Animal / Q000201:enzymology*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics*; D008324:Mammary Tumor Virus, Mouse; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D051058:Oncogene Protein v-akt / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D016159:Tumor Suppressor Protein p53; C576917:AURKA protein, human; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D051058:Oncogene Protein v-akt; D017346:Protein Serine-Threonine Kinases