Mitotic kinases are emerging therapeutic targets against metastatic breast cancer.

This review aims to outline mitotic kinase inhibitors' roles as potential therapeutic targets and assess their suitability as a stand-alone clinical therapy or in combination with standard treatments for advanced-stage solid tumors, including triple-negative breast cancer (TNBC). Breast cancer poses a significant global health risk, with TNBC standing out as the most aggressive subtype. Comprehending the role of mitosis is crucial for understanding how TNBC advances from a solid tumor to metastasis. Chemotherapy is the primary treatment used to treat TNBC. Some types of chemotherapeutic agents target cells in mitosis, thus highlighting the need to comprehend the molecular mechanisms governing mitosis in cancer. This understanding is essential for devising targeted therapies to disrupt these mitotic processes, prevent or treat metastasis, and improve patient outcomes. Mitotic kinases like Aurora kinase A, Aurora Kinase B, never in mitosis gene A-related kinase 2, Threonine-Tyrosine kinase, and Polo-kinase 1 significantly impact cell cycle progression by contributing to chromosome separation and centrosome homeostasis. When these kinases go awry, they can trigger chromosome instability, increase cell proliferation, and activate different molecular pathways that culminate in a transition from epithelial to mesenchymal cells. Ongoing clinical trials investigate various mitotic kinase inhibitors as potential biological treatments against advanced solid tumors. While clinical trials against mitotic kinases have shown some promise in the clinic, more investigation is necessary, since they induce severe adverse effects, particularly affecting the hematopoietic system.

Stress hormones are associated with inflammatory cytokines and attenuation of T-cell function in the ascites from patients with high grade serous ovarian cancer.

Mounting evidence suggests that chronic stress and subsequent distress can promote ovarian cancer progression. These altered psychological states have been linked to sustained release of stress hormones, activation of the ß-adrenergic receptors in ovarian cancer cells, and induction of pro-tumoral signaling pathways. In addition, data suggest that chronic stress promotes an inflammatory landscape highlighted by increased infiltration of tumor-associated macrophages into the ovarian tumor microenvironment (TME). In ovarian cancer, ascites is a unique TME comprised of tumor, and immune cells, which secrete pro-tumoral cytokines and chemokines that modulate tumor-associated immunity. However, our knowledge about how stress hormones impact the ascites TME remains limited. We hypothesized that the ascites harbors measurable levels of stress hormones, and accumulation of these in the ascites generates a pro-tumorigenic, inflammatory, and immunosuppressive TME. We evaluated ascites samples from 49 patients with high grade serous ovarian cancer (HGSOC) and quantified cortisol and stress hormones metabolites, metanephrine (MN), and normetanephrine (NMN) in all samples. We also measured 38 individual cytokines in the ascites, including several pro-inflammatory cytokines, such as IL-6, which were positively correlated to MN or NMN levels of those samples. Conversely, we found cortisol levels were negatively correlated to several pro-inflammatory cytokines. As T-cells are integral to the TME and our analyses identified cytokines in the ascites known to modulate T-cell function, we characterized ascites-derived T-cells and assessed the impact of stress hormones on the T-cell phenotype. Our data show an altered CD4+/CD8+ T-cell ratio and a heterogeneous expression of exhaustion markers in T-cells from the ascites, while ascites-derived CD8+ T-cells exposed to epinephrine had decreased co-expression CD38 and Granzyme B. To extend these findings to animal models, we subjected ovarian cancer-bearing mice to daily restraint stress, which resulted in increased tumor growth in two models. Congruent with our human analyses, we detected corticosterone, MN, and NMN in the ascites from tumor-bearing mice, and these stress hormones correlated with several inflammatory cytokines. Moreover, daily restraint stress leads to increased CD4+PD-1+/CD8+PD-1+ T-cell ratio in the ovarian tumor microenvironment. Overall, these data highlight a role of stress hormones in the ascites TME as a driver of tumor-associated inflammation, T-cell suppression, and disease progression.

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

E2F3 is a transcription factor that may initiate tumorigenesis if overexpressed. Previously, we demonstrated that E2F3 mRNA is overexpressed in breast cancer and that E2F3 overexpression results in centrosome amplification and unregulated mitosis, which can promote aneuploidy and chromosome instability to initiate and sustain tumors. Further, we demonstrated that E2F3 leads to overexpression of the mitotic regulator Shugoshin-1, which until recently had unknown roles in cancer. This study aims to evaluate the roles of E2F3 and Shugoshin-1 in breast cancer metastatic potential. Here we demonstrated that E2F3 and Shugoshin-1 silencing leads to reduced cell invasion and migration in two mesenchymal triple-negative breast cancer (TNBC) cell lines (MDA-MB-231 and Hs578t). Moreover, E2F3 and Shugoshin-1 modulate the expression of epithelial-to-mesenchymal transition-associated genes such as Snail, E-Cadherin, and multiple matrix metalloproteinases. Furthermore, E2F3 depletion leads to reductions in tumor growth and metastasis in NOD-scid Gamma mice. Results from this study suggest a key role for E2F3 and a novel role for Shugoshin-1 in metastatic progression. These results can further help in the improvement of TNBC targeted therapies by interfering with pathways that intersect with the E2F3 and Shugoshin-1 signaling pathways.