Abstract
Vascular endothelial growth factor-A (VEGF) signals vascular development and angiogenesis mainly by binding to VEGF receptor family member 2 (VEGFR-2). Adaptor proteins mediate many VEGFR-2’s functions in the development of blood vessels. Cancer cells secrete VEGF to activate VEGFR-2 pathway in their neighboring endothelial cells in the process of cancer-related angiogenesis. Interestingly, activation of VEGFR-2 signaling is found in breast cancer cells, but its role and regulation are not clear. We highlighted research advances of VEGFR-2, with a focus on VEGFR-2’s regulation by mutant p53 in breast cancer. In addition, we reviewed recent Food and Drug Administration-approved tyrosine kinase inhibitor drugs that can inhibit the function of VEGFR-2. Ongoing preclinical and clinical studies might prove that pharmaceutically targeting VEGFR-2 could be an effective therapeutic strategy in treating triple-negative breast cancer.
Highlights
Vascular endothelial growth factor-A (VEGF-A, known as vascular permeability factor) is a major factor in regulating functions of endothelial cells in vasculogenesis and angiogenesis [1, 2]
Much progress has been made in understanding the biology of VEGF receptor family member 2 (VEGFR-2) in breast cancer
One breakthrough is that mutant p53 recruits switch/ sucrose non-fermentable (SWI/SNF) to activate VEGFR-2 expression [53]
Summary
Vascular endothelial growth factor-A (VEGF-A, known as vascular permeability factor) is a major factor in regulating functions of endothelial cells in vasculogenesis and angiogenesis [1, 2]. In human umbilical vein endothelial cell models, VEGF stimulation triggers VEGFR-2 phosphorylation at Y951 and subsequent recruitment of VEGF-receptor-associated proteins (VRAPs; known as T-cell-specific adapter molecule, TSAd) [37]. VEGFR-2 cross talks with SRC or PI3K/Akt are mediated by VRAP/TSAd, and these cross talks are important to VEGF-induced cytoskeletal reorganization, migration, cell survival, and proliferation [34]. SH2 domain-containing adaptor proteins are recruited by these phosphorylated tyrosine residues, including VRAP/TSAd, PLC-γ, SHB, and NCK. These adaptors mediate the downstream effects of VEGFR-2, including cell proliferation, permeability, cell survival, and cell migration. In pig aortic endothelial cells expressing human VEGFR-2 molecules, VEGF stimulation induces VEGFR-2 phosphorylation at Y1175, and pY1175 recruits SH2 domain-containing adaptor protein B (SHB) [44]. Shb−/− mice have abnormal endothelial ultrastructures in liver sinusoids and heart capillaries [47]
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