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:  Publisher    
Abstract/OtherAbstract:
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.Oncogene advance online publication, 21 January 2013; doi:10.1038/onc.2012.628.
Authors:
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
Related Documents :
12554776 - Mitogen-activated protein kinase regulates nuclear association of human progesterone re...
22641216 - Lysyl oxidase enzymatic function increases stiffness to drive colorectal cancer progres...
24038146 - Ca(2+) signaling proteins plcγ2 and pkc are important to myeloid lineage commitment: d...
20880736 - Regulation of cross-talk in yeast mapk signaling pathways.
12974676 - Gbpi, a novel gastrointestinal- and brain-specific pp1-inhibitory protein, is activated...
23876806 - The p38 mapk and jnk pathways protect host cells against clostridium perfringens beta-t...
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-21
Journal Detail:
Title:  Oncogene     Volume:  -     ISSN:  1476-5594     ISO Abbreviation:  Oncogene     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-21     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
1] Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA [2] Department of Medical Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Oncogenic K-Ras requires activation for enhanced activity.
Next Document:  Aurora kinase A mediates epithelial ovarian cancer cell migration and adhesion.