The Nek2 centrosome-mitotic kinase contributes to the mesenchymal state, cell invasion, and migration of triple-negative breast cancer cells

• Authors: Yainyrette Rivera-Rivera, Ponce Health Sciences University; Mihaela Marina, MediTech Media; Shirley Jusino, Ponce Health Sciences University; Miyoung Lee, Emory University; Jaleisha Vélez Velazquez, University of Puerto Rico Ponce; Camille Chardon-Colon, Ponce Health Sciences University; Geraldine Vargas, Ponce Health Sciences University; Jaya Padmanabhan, H Lee Moffitt Cancer Centre & Research Institute; Srikumar P. Chellappan, H Lee Moffitt Cancer Centre & Research Institute; Harold Saavedra, Emory University
• Journal Title: Scientific Reports
• Volume: Volume 11, Number 1
• Publisher: Nature Research | 2021-04-27, Pages 9016-9016
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1038/s41598-021-88512-0
• Subjects: Biology, Genetics; Health Sciences, Oncology; Biology, General; Health Sciences, Human Development
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; Beta cateninn; Chromosomal instability; Genomic instability; Drug resistance; Amplification; Expression; Aneuploidy; Growth; Cycle

Abstract

Nek2 (NIMA-related kinase 2) is a serine/threonine-protein kinase that localizes to centrosomes and kinetochores, controlling centrosome separation, chromosome attachments to kinetochores, and the spindle assembly checkpoint. These processes prevent centrosome amplification (CA), mitotic dysfunction, and chromosome instability (CIN). Our group and others have suggested that Nek2 maintains high levels of CA/CIN, tumor growth, and drug resistance. We identified that Nek2 overexpression correlates with poor survival of breast cancer. However, the mechanisms driving these phenotypes are unknown. We now report that overexpression of Nek2 in MCF10A cells drives CA/CIN and aneuploidy. Besides, enhanced levels of Nek2 results in larger 3D acinar structures, but could not initiate tumors in a p53+/+ or a p53-/- xenograft model. Nek2 overexpression induced the epithelial-to-mesenchymal transition (EMT) while its downregulation reduced the expression of the mesenchymal marker vimentin. Furthermore, either siRNA-mediated downregulation or INH6's chemical inhibition of Nek2 in MDA-MB-231 and Hs578t cells showed important EMT changes and decreased invasion and migration. We also showed that Slug and Zeb1 are involved in Nek2 mediated EMT, invasion, and migration. Besides its role in CA/CIN, Nek2 contributes to breast cancer progression through a novel EMT mediated mechanism.