TRPS1Expression Promotes Angiogenesis And Affects VEGFA Expression In Breast Cancer

Background:Angiogenesis is a hallmark of the malignant process in breast cancer。Tumor cells outgrow the diffusion limit for oxygen of nearby blood vessels and become hypoxic. This phenomenon results in activation of pathologic angiogenesis, which causes normally quiescent vasculature to sprout new vessels. This process helps sustain the expansion of neoplastic growths。The angiogenic process is well-regulated by a complex growth factor networkin which vascular endothelial growth factor A (VEGFA) plays an important role. Anti-VEGF therapy using small inhibitors or monoclonal antibodies inhibits pathologic angiogenesis. Unfortunately, this approach is unsatisfactory in multiple tumor types.TRPS1is a GATA-type transcription factor and is involved in trichorhinophalangeal syndrome type1.A number of reports suggest that TRPS1is highly overexpressed in breast cancer. TRPS1induces the epithelial-to-mesenchymal transition (EMT) by releasing the negative regulation of ZEB2as a target of miR-221/222in breast cancer. This study aims to investigate the relationship between TRPS1and angiogenesis, and whether TRPS1can directly regulate VEGFA in breast cancers.Methods:1TRPS1and CD31expression levels were analyzed by immunohistochemistry in117paraffin-embedded breast tissues.2Breast cancer cells were transfected with full-length TRPS1and shRNA. 3Their ability to induce human umbilical vein endothelial cell (HUVEC) migration was analyzed using chemotactic migration assay.4The changes in VEGFA mRNA and protein levels were examined by quantitative real-time polymerase chain reaction and western blot analysis.5Chromatin immunoprecipitation assay (ChIP) was carried out to determine whether endogenous TRPS1was present in the VEGFA promoter.Results:1Statistical analyses indicated that TRPS1expression was directly correlated with CD31(P=0.001), which was further confirmed by Spearman correlation analysis (R=0.313, P=0.001).2The overexpression of TRPS1caused a significant increase in the ability to induce HUVEC migration (P<0.0001) accompanied with VEGFA upregulation (P<0.05) in transfected cells. By contrast, knockdown of TRPS1resulted in the decrease in the ability to induce HUVEC migration (P<0.01) and a significant downregulation in VEGFA expression(P<0.05).3ChIP assay indicated that endogenous TRPS1was present in the VEGFA promoter.Conclusions:This study is the first to provide evidence of the direct influence of TRPS1on VEGFA expression, which contributes to angiogenesis. Further investigation on the functions of TRPS1in angiogenesis may provide a promising target for breast cancer treatment.