title: The mitotic kinase Aurora--a promotes distant metastases by inducing epithelial-to-mesenchymal transition in ERα(+) breast cancer cells.
abstract: 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.
authors: 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.
authors: A B
authors: AB
authors: D'Assoro
authors: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: T
authors: T
authors: Liu
authors: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: C
authors: C
authors: Quatraro
authors: 1] Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA [2] Department of Cellular and Developmental Biology, Palermo, Italy.
authors: A
authors: A
authors: Amato
authors: 1] Department of Medical Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA [2] Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: M
authors: M
authors: Opyrchal
authors: Department of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: A
authors: A
authors: Leontovich
authors: Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: Y
authors: Y
authors: Ikeda
authors: Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: S
authors: S
authors: Ohmine
authors: Department of Experimental Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: W
authors: W
authors: Lingle
authors: Department of Medical Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: V
authors: V
authors: Suman
authors: Department of Oncology, Millennium Pharmaceuticals Inc., Cambridge, MA, USA.
authors: J
authors: J
authors: Ecsedy
authors: Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: I
authors: I
authors: Iankov
authors: Department of Cellular and Developmental Biology, Palermo, Italy.
authors: A
authors: A
authors: Di Leonardo
authors: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: J
authors: J
authors: Ayers-Inglers
authors: Department of General Surgery, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: A
authors: A
authors: Degnim
authors: Department of Medical Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: D
authors: D
authors: Billadeau
authors: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA.
authors: J
authors: J
authors: McCubrey
authors: Department of Medical Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: J
authors: J
authors: Ingle
authors: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: J L
authors: JL
authors: Salisbury
authors: 1] Department of Medical Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA [2] Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: E
authors: E
authors: Galanis
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D051927:CD24 Antigen / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D051902:Smad5 Protein / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D064096:Aurora Kinase A; D051927:CD24 Antigen; D047628:Estrogen Receptor alpha; D019908:Proto-Oncogene Proteins c-raf; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D055748:SOXB1 Transcription Factors; D051902:Smad5 Protein; C497797:SMAD5 protein, human; C527782:SOX2 protein, human; C508053:ERBB2 protein, human; C576917:AURKA protein, human