|The mitotic kinase Aurora--a promotes distant metastases by inducing epithelial-to-mesenchymal transition in ERα(+) breast cancer cells.|
|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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|Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2013-01-21|
|Title: Oncogene Volume: 33 ISSN: 1476-5594 ISO Abbreviation: Oncogene Publication Date: 2014 Jan|
|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|
|Languages: eng Pagination: 599-610 Citation Subset: IM|
|APA/MLA Format Download EndNote Download BibTex|
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
Neoplastic Stem Cells / cytology, metabolism
Phosphorylation / genetics
Proto-Oncogene Proteins c-raf / metabolism
RNA, Small Interfering
Receptor, erbB-2 / biosynthesis
SOXB1 Transcription Factors / genetics, metabolism
Smad5 Protein / metabolism
Xenograft Model Antitumor Assays
|CA116201/CA/NCI NIH HHS; P30 CA015083/CA/NCI NIH HHS; P50 CA116201/CA/NCI NIH HHS|
|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 18.104.22.168/ERBB2 protein, human; EC 22.214.171.124/Receptor, erbB-2; EC 126.96.36.199/AURKA protein, human; EC 188.8.131.52/Aurora Kinase A; EC 184.108.40.206/Proto-Oncogene Proteins c-raf|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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