Central role of p53 on regulation of vascular permeability factor/vascularendothelial growth factor (VPF/VEGF) expression in mammary carcinoma

The process of angiogenic switching is one of the most important factors in the growth and development of breast tumors. Vascular permeability factor/ vascular endothelial growth factor (VPFNEGF) is considered to be the most important directly acting angiogenic protein that has been shown to be up-r egulated in breast cancer cells. Hypoxia seems to be an important stimulus for inducing VPFNEGF mRNA expression in human mammary tumors. Here, we have studied the roles of the tumor suppressor gene p53 and the proto-oncogene c-Src in regulating the transcription of VPFA-EGF in breast cancer cell lin es MCF-7 and MDA-MB 435 under both normoxic and hypoxic conditions. p53 sig nificantly inhibited the transcription of VPF/ VEGF involving the transcrip tion factor Spl. Increased binding of Sp1 to the VPFNEGF promoter has been observed when the cells were exposed to hypoxia. It has been shown that p53 makes a complex with Sp1 and inhibits its binding to the VPFNEGF promoter to prevent the transcriptional activation. Furthermore, c-Src kinase activi ty was found to be increased in the hypoxic condition, and in the presence of antisense of Src, there was downregulation of the total mRNA level and a lso the promoter activity of VPF/ VEGF. The present study indicates that p5 3 can also inhibit the hypoxic induction of Src kinase activity and thereby may prevent VPF/VEGF transcription. Taken together, our data suggest a cen tral role of p53, through which it can inhibit VPFNEGF expression by regula ting the transcriptional activity of Spl and also by down-regulating the Sr c kinase activity, under both normoxic and hypoxic conditions.