title: AurkA controls self-renewal of breast cancer-initiating cells promoting wnt3a stabilization through suppression of miR-128.
abstract: AurkA overexpression was previously found in breast cancer and associated to its ability in controlling chromosome segregation during mitosis, however whether it may affect breast cancer cells, endorsed with stem properties (BCICs), is still unclear. Surprisingly, a strong correlation between AurkA expression and β-catenin localization in breast cancer tissues suggested a link between AurkA and Wnt signaling. In our study, AurkA knock-down reduced wnt3a mRNA and suppressed metastatic signature of MDA-MB-231 cells. As a consequence, the amount of BCICs and their migratory capability dramatically decreased. Conversely, wnt3a mRNA stabilization and increased CD44(+)/CD24(low/-) subpopulation was found in AurkA-overexpressing MCF7 cells. In vivo, AurkA-overexpressing primary breast cancer cells showed higher tumorigenic properties. Interestingly, we found that AurkA suppressed the expression of miR-128, inhibitor of wnt3a mRNA stabilization. Namely, miR-128 suppression realized after AurkA binding to Snail. Remarkably, a strong correlation between AurkA and miR-128 expression in breast cancer tissues confirmed our findings. This study provides novel insights into an undisclosed role for the kinase AurkA in self-renewal and migration of BCICs affecting response to cancer therapies, metastatic spread and recurrence. In addition, it suggests a new therapeutic strategy taking advantage of miR-128 to suppress AurkA-Wnt3a signaling.
authors.affiliation: Lab of Experimental Oncology &Pharmacogenomics IRCCS Fondazione "Salvatore Maugeri", Pavia, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Eterno
authors.affiliation: Lab of Experimental Oncology &Pharmacogenomics IRCCS Fondazione "Salvatore Maugeri", Pavia, Italy.|Unit of Oncology, IRCCS S. Maugeri Foundation, 27100 Pavia.
authors.forename: A
authors.initials: A
authors.lastname: Zambelli
authors.affiliation: Unit of Pathology, IRCCS S. Maugeri Foundation, 27100 Pavia.
authors.forename: L
authors.initials: L
authors.lastname: Villani
authors.affiliation: Lab of Experimental Oncology &Pharmacogenomics IRCCS Fondazione "Salvatore Maugeri", Pavia, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Tuscano
authors.affiliation: Lab of Experimental Oncology &Pharmacogenomics IRCCS Fondazione "Salvatore Maugeri", Pavia, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Manera
authors.affiliation: Lab of Experimental Oncology &Pharmacogenomics IRCCS Fondazione "Salvatore Maugeri", Pavia, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Spitaleri
authors.affiliation: Lab of Experimental Oncology &Pharmacogenomics IRCCS Fondazione "Salvatore Maugeri", Pavia, Italy.|Unit of Oncology, IRCCS S. Maugeri Foundation, 27100 Pavia.
authors.forename: L
authors.initials: L
authors.lastname: Pavesi
authors.affiliation: Lab of Experimental Oncology &Pharmacogenomics IRCCS Fondazione "Salvatore Maugeri", Pavia, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Amato
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D064096:Aurora Kinase A / Q000502:physiology*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D000066673:Cell Self Renewal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000502:physiology*; D055550:Protein Stability; D060509:Wnt3A Protein / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; C545189:MIRN128 microRNA, human; D035683:MicroRNAs; C555510:WNT3A protein, human; D060509:Wnt3A Protein; D051176:beta Catenin; C576917:AURKA protein, human; D064096:Aurora Kinase A