Abstract
Triple-negative breast cancer (TNBC) remains a significant clinical challenge because of its high vascularity and metastatic and recurrent rates. Tumor angiogenesis is considered an important mediator in the regulation of tumor cell survival and metastasis in TNBC. Angiogenesis is induced by the binding of vascular endothelial growth factor to vascular endothelial growth factor receptor 2 (VEGFR2). Focal adhesion kinase (FAK) plays an important role in regulating various cell functions in normal and cancer cells. Previous studies have focused on investigating the function of endothelial FAK in tumor cell angiogenesis. However, the association between tumor FAK and VEGFR2 in tumor angiogenesis and the possible mechanisms of this remain unclear. In this study, we used a public database and human specimens to examine the association between FAK and VEGFR2. At the same time, we verified the association between FAK and VEGFR2 through several experimental methods, such as quantitative real-time polymerase chain reaction, Western blotting, and next-generation sequencing. In addition, we used the endothelial cell model, zebrafish, and xenograft animal models to investigate the role of FAK in TNBC angiogenesis. We found that FAK and VEGFR2 were positively correlated in patients with TNBC. VEGFR2 and several other angiogenesis-related genes were regulated by FAK. In addition, FAK regulated VEGFR2 and VEGF protein expression in TNBC cells. Functional assays showed that FAK knockdown inhibited endothelial tube formation and zebrafish angiogenesis. An animal model showed that FAK inhibitors could suppress tumor growth and tumor vascular formation. FAK promotes angiogenesis in TNBC cells by regulating VEGFR2 expression. Therefore, targeting FAK could be another antiangiogenic strategy for TNBC treatment.
Highlights
Breast cancer is a heterogeneous disease and the most common cancer type worldwide [1]
Focal adhesion kinase (FAK) has been considered a mediator of tumor angiogenesis in vascular cells surrounding solid tumors [16], and nuclear FAK activity plays a role in endothelial cells during tumor angiogenesis [27]
By examining several gene expression data sets, we found that there was a positive correlation between FAK and vascular endothelial growth factor receptor 2 (VEGFR2), especially in patients with
Summary
Breast cancer is a heterogeneous disease and the most common cancer type worldwide [1]. Diagnostic methods and therapeutic strategies have made significant progress in breast cancer, it still represents the most common leading cause of cancer-related deaths among women worldwide [2]. Among all breast cancer subtypes, triple-negative breast cancer (TNBC) is the most aggressive subtype with a high probability of angiogenesis, metastasis, and drug resistance and a lack of specific targets and targeted therapies [3]. Previous studies have indicated that angiogenesis is essential for the dissemination and establishment of tumor metastases, and these phenomena are regulated by the interactions between tumor cells and tumor microenvironment (TME) [4,5]. Understanding the TME and its regulators will be useful for developing new targeted therapies to decrease tumor progression and metastasis in patients with TNBC.
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