Mitotic kinases as drivers of the epithelial-to-mesenchymal transition and as therapeutic targets against breast cancers

Abstract

Biological therapies against breast cancer patients with tumors positive for the estrogen and progesterone hormone receptors and Her2 amplification have greatly improved their survival. However, to date, there are no effective biological therapies against breast cancers that lack these three receptors or triple-negative breast cancers (TNBC). TNBC correlates with poor survival, in part because they relapse following chemo- and radio-therapies. TNBC is intrinsically aggressive since they have high mitotic indexes and tend to metastasize to the central nervous system. TNBCs are more likely to display centrosome amplification, an abnormal phenotype that results in defective mitotic spindles and abnormal cytokinesis, which culminate in aneuploidy and chromosome instability (known causes of tumor initiation and chemo-resistance). Besides their known role in cell cycle control, mitotic kinases have been also studied in different types of cancer including breast, especially in the context of epithelial-to-mesenchymal transition (EMT). EMT is a cellular process characterized by the loss of cell polarity, reorganization of the cytoskeleton, and signaling reprogramming (upregulation of mesenchymal genes and downregulation of epithelial genes). Previously, we and others have shown the effects of mitotic kinases like Nek2 and Mps1 (TTK) on EMT. In this review, we focus on Aurora A, Aurora B, Bub1, and highly expressed in cancer (Hec1) as novel targets for therapeutic interventions in breast cancer and their effects on EMT. We highlight the established relationships and interactions of these and other mitotic kinases, clinical trial studies involving mitotic kinases, and the importance that represents to develop drugs against these proteins as potential targets in the primary care therapy for TNBC.

Keywords: Aurora kinases; Bub1; Centrosome/mitotic kinases; Hec1; breast cancer; epithelial-to-mesenchymal transition.

Figure 1.

Model portraying how mitotic kinases connect to control epithelial-to-mesenchymal transition (EMT), invasion, and metastasis in breast cancer. Dysregulation of mitotic kinases activates a series of events that ultimately lead to EMT and metastasis allowing them to become potential oncogenes. Aurora A directly triggers EMT by activating the transcription factors Twist and Slug. Aurora A correlates with Wnt/β-catenin and PI3K/Akt signaling and was found to lead to EMT progression. Other studies have found that Aurora A regulated EMT is mediated by MAPK phosphorylation. Similarly, inhibition of Aurora A leads to the suppression of EMT through the downregulation of the MAPK pathway. Targeting Aurora B inhibits the OCT/AKT/GSK3β/Snail1 signaling, reverses EMT, and suppresses cancer progression, while both Aurora B and Nek2 regulate Hec1 for the maintenance of mitotic function and cell survival. Phosphorylation of Hec1 by Nek2 is essential for its mitotic function. Nek2 may signal EMT through Hec1 or independently of Hec1. Bub1 controls TGF-β which induces EMT. Inhibitors in clinical trials are shown in red. (A color version of this figure is available in the online journal.)