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.

Budding uninhibited by benzimidazoles 1 overexpression is associated with poor prognosis and malignant phenotype: A promising therapeutic target for lung adenocarcinoma

“…According to pan‐cancer analysis, BUB1 may play important roles in interaction with the The anaphase‐promoting complex/cyclosome (APC/C) activator protein Cdc20, which has carcinogenic and prognostic significance 13 . Moreover, the overexpression of BUB1 proteins is strongly associated with the malignant phenotype and poor prognosis in various malignancies, including bladder cancer, osteosarcoma, leukemia, gastric cancer, liver cancer, breast cancer, and pancreatic ductal adenocarcinoma 14–20 . The above literature indicates that BUB1 may contribute to the progression of multiple human tumors through a variety of complex mechanisms.…”

Identification of a chromatin regulator signature in prognosis and immune infiltration in breast cancer

“…One TTK inhibitor (CFI-402257) has been tested in BC cell lines and entered clinical trials [50,51]. Moreover, TTK is also considered a top target for radiosensitization as the inhibition of TTK could enhance the sensitivity to radiotherapy in many basal-like BC cell lines [52,53]. Jumonji C domain-containing demethylase 4 (JMJD4) is a C4 Lysyl Hydroxylase and is considered playing a broad role in transcription termination [54], the maintenance of embryonic stem cell (ESC) and the development of embryo [55].…”

E2F3 drives the epithelial-to-mesenchymal transition, cell invasion, and metastasis in breast cancer

“…Already some inhibitors for Aurora B are in clinical trial phases (this can be further reviewed in Colón-Marrero et al. 24 ) Also, some studies have shown a role for some of these kinases in EMT and metastasis in breast cancer. For example, Aurora B has been shown to induce EMT via OCT4/AKT/GSK3β/Snail1 signaling.…”

“…19–23 SGO1 is a common target of these kinases. 24 However, the exact mechanism of how E2F3 and SGO1 regulate EMT in TNBC remains poorly understood. Hence, we investigated the effects of E2F3 and SGO1 depletion in EMT, cell invasion, and cell migration in TNBC to dissect the underlying mechanism behind this observation.…”