Triple‐negative breast cancer (TNBC) is a very aggressive subtype with high recurrence rate and no molecular targets for therapies. This subtype is characterized by high expression/secretion of the proinvasive/metastatic interleukin‐6 (IL‐6) cytokine. In the present study, we have shown that tocilizumab inhibits the IL‐6/STAT3 signaling and suppresses the cancer/inflammatory epigenetic IL‐6/STAT3/NF‐κB positive feedback loop. Furthermore, tocilizumab inhibited the proliferative and the migratory/invasiveness capacities as well as the epithelial‐to‐mesenchymal transition (EMT) process in TNBC cells. Importantly, tocilizumab suppressed the stemness‐related characteristics of TNBC cells, through the inhibition of the Wnt/β‐catenin breast cancer stem cell‐related pathway. Additionally, we have shown that tocilizumab suppresses the paracrine activation of normal breast stromal fibroblasts to myofibroblats. Moreover, tocilizumab sensitized TNBC cells to the cytotoxic effect of cisplatin in vitro. Furthermore, pharmacological inhibition of IL‐6 by tocilizumab had great inhibitory effect on tumor growth and the EMT process in humanized orthotopic breast tumors in mice. In addition, tocilizumab potentiated the proapoptotic effect of cisplatin in humanized breast tumors. Together, these findings indicate that tocilizumab can suppress the prometastatic capacity of TNBC cells and enhances the cytotoxic effect of cisplatin against these cells. Therefore, tocilizumab could be of great therapeutic value for these hard‐to‐treat TNBC patients.

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Triple‐negative breast cancer (TNBC) is the most aggressive subtype of the disease with lack of recognized molecular targets for therapy. TNBC cells are known to secrete high levels of the proinflammatory cytokines interleukin‐6 (IL‐6) and IL‐8, which promote angiogenesis and favor the growth and spread of the disease. In the present study, we have shown that the humanized anti‐IL‐6 receptor tocilizumab (Actemra) is also a potent inhibitor of IL‐8 in TNBC cells. Similar effect was also obtained by specific IL‐6 inhibition either by small interfering RNA or by neutralizing antibody. Likewise, neutralizing IL‐8 with specific antibody downregulated IL‐8 and inhibited the IL‐6/signal transducer and activator of transcription 3 and nuclear factor‐κB pathways. Interestingly, simultaneous co‐inhibition of IL‐6 and IL‐8 did not increase the effects of the single inhibitors. Additionally, we present clear evidence that tocilizumab has potent antiangiogenic effect. Indeed, tocilizumab abolished the ability of TNBC cells to induce the differentiation of endothelial cells into network‐like tubular structures in vitro and impaired neovascularization in humanized breast orthotopic tumor xenografts. This was associated with tocilizumab‐dependent downregulation of the main proangiogenic factor vascular endothelial growth factor A and its coactivator hypoxia‐inducible factor 1 both in vitro and in vivo. Therefore, tocilizumab could be of great therapeutic value for TNBC patients through targeting angiogenesis.

Background Locally advanced breast cancer (LABC), the most aggressive form of the disease, is a serious threat for women's health worldwide. The AU-rich RNA-binding factor 1 (AUF1) promotes the formation of chemo-resistant breast cancer stem cells. Thereby, we investigated the power of AUF1 expression, in both cancer cells and their stromal fibroblasts, as predictive biomarker for LABC patients’ clinical outcome following neoadjuvant treatment. Methods We have used immunohistochemistry to assess the level of AUF1 on formalin-fixed paraffin-embedded tissues. Immunoblotting was utilized to show the effect of AUF1 ectopic expression in breast stromal fibroblasts on the expression of various genes both in vitro and in orthotopic tumor xenografts. Cytotoxicity was evaluated using the WST1 assay, while a label-free real-time setting using the xCELLigence RTCA technology was utilized to assess the proliferative, migratory and invasive abilities of cells. Results We have shown that high AUF1 immunostaining (≥ 10%) in both cancer cells and their adjacent cancer-associated fibroblasts (CAFs) was significantly associated with higher tumor grade. Kaplan–Meier univariate analysis revealed a strong correlation between high AUF1 level in CAFs and poor patient’s survival. This correlation was highly significant in patients with triple negative breast cancer, who showed poor disease-free survival (DFS) and overall survival (OS). High expression of AUF1 in CAFs was also associated with poor OS of ER+/Her2− patients. Similarly, AUF1-positive malignant cells tended to be associated with shorter DFS and OS of ER+/Her2+ patients. Interestingly, neoadjuvant therapy downregulated AUF1 to a level lower than 10% in malignant cells in a significant number of patients, which improved both DFS and OS. In addition, ectopic expression of AUF1 in breast fibroblasts activated these cells and enhanced their capacity to promote, in an IL-6-dependent manner, the epithelial-to-mesenchymal transition and stemness processes. Furthermore, these AUF1-expressing cells enhanced the chemoresistance of breast cancer cells and their growth in orthotopic tumor xenografts. Conclusions The present findings show that the CAF-activating factor AUF1 has prognostic/predictive value for breast cancer patients and could represent a great therapeutic target in order to improve the precision of cancer treatment.

Anaplastic thyroid carcinoma (ATC) is the rarest type of thyroid cancer, but is the common cause of death from these tumors. The aggressive behavior of ATC makes it resistant to the conventional therapeutic approaches. Thus, the present study was designed to evaluate the anti-ATC efficacy of the piperidone analogue of curcumin (PAC). We have shown that PAC induces apoptosis in thyroid cancer cells in a time-dependent fashion through the mitochondrial pathway. Immunoblotting analysis revealed that PAC suppressed the epithelial-to-mesenchymal transition (EMT) process in ATC cells by upregulating the epithelial marker E-cadherin and reducing the level of the mesenchymal markers N-cadherin, Snail, and Twist1. This anti-EMT effect was confirmed by showing PAC-dependent inhibition of the proliferation and migration abilities of ATC cells. Furthermore, PAC inhibited the AKT/mTOR pathway in ATC cells. Indeed, PAC downregulated mTOR and its downstream effectors p70S6K and 4E-BP1 more efficiently than the well-known mTOR inhibitor rapamycin. In addition to the promising in vitro anticancer efficacy, PAC significantly suppressed the growth of humanized thyroid tumor xenografts in mice. Together, these findings indicate that PAC could be considered as promising therapeutic agent for anaplastic thyroid carcinomas.