6533b7d4fe1ef96bd1263339
RESEARCH PRODUCT
The mitotic kinase Aurora-A promotes distant metastases by inducing epithelial-to-mesenchymal transition in ERα+ breast cancer cells
Cosima QuatraroWilma L. LingleMateusz OpyrchalIanko D. IankovYasuhiro IkedaAngela AmatoT LiuJames A. MccubreyVera J. SumanA B D'assoroJn IngleJeffrey EcsedyAmy C. DegnimDaniel D. BilladeauSeiga OhmineA Di LeonardoJ Ayers-inglersAlexey A. LeontovichEvanthia GalanisJeffrey L. Salisburysubject
Smad5 ProteinCancer ResearchEpithelial-Mesenchymal TransitionMAP Kinase Signaling SystemReceptor ErbB-2Active Transport Cell NucleusEstrogen receptorMice NudeBreast NeoplasmsBiologyArticleMicebreast cancerSOX2Cell MovementCell Line TumorGeneticsAnimalsHumansEpithelial–mesenchymal transitionKinase activityNeoplasm MetastasisPhosphorylationRNA Small InterferingMolecular BiologyAurora Kinase Ametastases mitosisSOXB1 Transcription FactorsEstrogen Receptor alphaCD24 AntigenXenograft Model Antitumor AssaysstemneGene Expression Regulation NeoplasticProto-Oncogene Proteins c-rafSettore BIO/18 - GeneticaTumor progressionembryonic structuresCancer researchMCF-7 CellsNeoplastic Stem CellsProto-Oncogene Proteins c-rafFemaleRNA InterferenceSignal transductionEstrogen receptor alphaNeoplasm Transplantationdescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2013-01-21 |