Document Detail

The mitotic kinase Aurora--a promotes distant metastases by inducing epithelial-to-mesenchymal transition in ERα(+) breast cancer cells.
MedLine Citation:
PMID:  23334326     Owner:  NLM     Status:  MEDLINE    
In this study, we demonstrate that constitutive activation of Raf-1 oncogenic signaling induces stabilization and accumulation of Aurora-A mitotic kinase that ultimately drives the transition from an epithelial to a highly invasive mesenchymal phenotype in estrogen receptor α-positive (ERα(+)) breast cancer cells. The transition from an epithelial- to a mesenchymal-like phenotype was characterized by reduced expression of ERα, HER-2/Neu overexpression and loss of CD24 surface receptor (CD24(-/low)). Importantly, expression of key epithelial-to-mesenchymal transition (EMT) markers and upregulation of the stemness gene SOX2 was linked to acquisition of stem cell-like properties such as the ability to form mammospheres in vitro and tumor self-renewal in vivo. Moreover, aberrant Aurora-A kinase activity induced phosphorylation and nuclear translocation of SMAD5, indicating a novel interplay between Aurora-A and SMAD5 signaling pathways in the development of EMT, stemness and ultimately tumor progression. Importantly, pharmacological and molecular inhibition of Aurora-A kinase activity restored a CD24(+) epithelial phenotype that was coupled to ERα expression, downregulation of HER-2/Neu, inhibition of EMT and impaired self-renewal ability, resulting in the suppression of distant metastases. Taken together, our findings show for the first time the causal role of Aurora-A kinase in the activation of EMT pathway responsible for the development of distant metastases in ERα(+) breast cancer cells. Moreover, this study has important translational implications because it highlights the mitotic kinase Aurora-A as a novel promising therapeutic target to selectively eliminate highly invasive cancer cells and improve the disease-free and overall survival of ERα(+) breast cancer patients resistant to conventional endocrine therapy.
A B D'Assoro; T Liu; C Quatraro; A Amato; M Opyrchal; A Leontovich; Y Ikeda; S Ohmine; W Lingle; V Suman; J Ecsedy; I Iankov; A Di Leonardo; J Ayers-Inglers; A Degnim; D Billadeau; J McCubrey; J Ingle; J L Salisbury; E Galanis
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-21
Journal Detail:
Title:  Oncogene     Volume:  33     ISSN:  1476-5594     ISO Abbreviation:  Oncogene     Publication Date:  2014 Jan 
Date Detail:
Created Date:  2014-01-30     Completed Date:  2014-04-01     Revised Date:  2014-07-04    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  599-610     Citation Subset:  IM    
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MeSH Terms
Active Transport, Cell Nucleus
Antigens, CD24 / genetics
Aurora Kinase A / antagonists & inhibitors,  genetics,  metabolism*
Breast Neoplasms / enzymology,  pathology*
Cell Line, Tumor
Cell Movement / genetics
Epithelial-Mesenchymal Transition / genetics*
Estrogen Receptor alpha / biosynthesis,  genetics,  metabolism*
Gene Expression Regulation, Neoplastic
MAP Kinase Signaling System / genetics
MCF-7 Cells
Mice, Nude
Neoplasm Metastasis
Neoplasm Transplantation
Neoplastic Stem Cells / cytology,  metabolism
Phosphorylation / genetics
Proto-Oncogene Proteins c-raf / metabolism
RNA Interference
RNA, Small Interfering
Receptor, erbB-2 / biosynthesis
SOXB1 Transcription Factors / genetics,  metabolism
Smad5 Protein / metabolism
Xenograft Model Antitumor Assays
Grant Support
Reg. No./Substance:
0/Antigens, CD24; 0/Estrogen Receptor alpha; 0/RNA, Small Interfering; 0/SMAD5 protein, human; 0/SOX2 protein, human; 0/SOXB1 Transcription Factors; 0/Smad5 Protein; EC protein, human; EC, erbB-2; EC protein, human; EC Kinase A; EC Proteins c-raf

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