SHR-2415

Breast cancer (BC) is highly prevalent in women and is often fatal.Vasculogenic mimicry (VM) is associated with cancer progression.The expression of Cavolin-2 (CAV-2) affects the occurrence and development of BC, but the specific mechanism of CAV-2 in BC is still poorly understood.The aim of our study was to explore the specific mechanism of the effect of CAV-2 on the occurrence of VM and the malignant biol. behavior of BC.First, we detected the gene expression of CAV-2 in BC tissues and cell lines.The overexpressed CAV-2 plasmid (oe-CAV-2) and si-CAV-2 were then transfected into michigan cancer foundation-7 (MCF-7) cells to determine the effects of different expression levels of CAV-2 on BC cells.In addition, to further determine the feedback loop mechanism between CAV-2 and epidermal growth factor receptor (EGFR), the cells were treated with (1) AG1478, which inhibits EGFR phosphorylation, (2) an EGFR phosphorylation activator epidermal growth factor (EGF), (3) a ubiquitination proteasome inhibitor MG-132, and (4) an extracellular regulated protein kinases1/2 (ERK1/2) inhibitor SHR2415.In the cell experiment, VM and the biol. behavior of BC cells were mainly observed by tumor spheroid formation, tube formation, Transwell, 5-ethynyl-2"-deoxyuridine (EdU), and scratch tests.In addition, we performed Western blot anal. of epithelial-mesenchymal transition (EMT)-associated proteins and angiogenesis analog markers.Finally, s.c. injection of breast cancer cells into nude mice was used to establish an animal model of BC so that the effect of CAV-2 on the progression of BC could be verified in vivo.CAV-2 was reduced in BC patient cancer tissue and in human BC cells (p < 0.001).Overexpression of CAV-2 effectively inhibited the progression of BC cells and reduced the formation of tumor spheres and tubules, whereas knockdown of CAV-2 had the opposite effect.CAV-2 and EGFR could interact, and the expression of EGFR was higher after overexpression of CAV-2 (p <0.001), but P-EGFR expression was lower (p <0.01).Treatment with the EGFR phosphorylation inhibitor AG1478 further enhanced the effect of oe-CAV-2.Treatment with the EGFR phosphorylation activator EGF reversed the effects of oe-CAV-2.After EGF treatment, the CAV-2 ubiquitination level was increased, but its gene expression decreased (p <0.01).EGF promoted VM occurrence and malignant biol. behavior of BC cells, and the EGF effect was reversed after overexpression of CAV-2.EGF also promoted the upregulation of P-ERK1/2 expression (p < 0.001), and the promotion effect of EGF on the behavior and angiogenic mimicry of BC cells was reversed after treatment with SHR2415, an ERK1/2 inhibitor.Animal experiments have also confirmed that CAV-2 can inhibit tumor growth and the phosphorylation of EGFR and ERK1/2, and this effect can also be reversed by treatment with EGF to a certain extent.CAV-2 can inhibit the phosphorylation of ERK1/2 by antagonizing EGFR phosphorylation and downregulating the expression of p-EGFR, thereby inhibiting VM and the malignant biol. behavior of BC.In the process of regulating EGFR phosphorylation by CAV-2, p-EGFR can induce CAV-2 ubiquitination, i.e., CAV-2 regulates the ERK signaling pathway through an EGFR feedback loop and influences the angiogenic mimicry and malignant biol. behavior of BC.