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

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.

Modest increase of KIF11 expression exposes fragilities in the mitotic spindle, causing chromosomal instability

“…Previously, overexpression of CCND1 in MEFs increased the expression of genes involved in chromatin reorganisation and chromosome segregation, increasing the incidence of 4N/8N cells, and chromosomal translocations (Casimiro and Pestell, 2015). Similarly, overexpression of NEK2 resulted in centrosome amplification and binucleation in MCF10A cells (Rivera-Rivera et al, 2021). Previously, 500-10000 fold overexpression of MAD2 induced tetraploidy and aneuploidy (Sotillo et al, 2007).…”

Identification of biological pathways and processes regulated by NEK5 in breast epithelial cells via an integrated proteomic approach

“…Several NEK5-associated pathways identified by our integrated proteomic studies have been linked to other NEK family members. For example, NEK2 has an important role in centrosome separation [30,52] and is implicated in breast cancer progression [53], while NEK6, NEK7 and NEK9 are involved in mitotic spindle assembly, which requires regulation of microtubule polymerization [54][55][56]. In addition, most NEK family members have been linked to the DNA Damage Response [14,[57][58][59].…”

Evaluating the Expression and Prognostic Value of Genes Encoding Microtubule-Associated Proteins in Lung Cancer

“…Targeting NEK2 inhibits tumorigenesis through the Wnt1/beta-catenin signaling pathway in cervical cancer [ 71 ]. Furthermore, overexpression of NEK2 in triple-negative breast cancer cells promotes cell migration and invasion [ 72 ]. Additionally, NEK2 has also been found to be overexpressed and possess significant prognostic value in lung cancer [ 68 , 73 ].…”