In this study, we used a self-contained tetracycline-regulated retroviral vector system to elucidate the role of vascular endothelial growth factor (VEGF) in controlling s.c. growth of human T-47D breast carcinoma cells. VEGF expression was tightly regulated by this system, both in vitro and in nude mouse xenografts. A 2.4-fold increase in tumor volume was associated with VEGF overexpression. Tumor growth was almost completely inhibited when VEGF was suppressed from the time of T-47D cell inoculation, and a 6-fold reduction in tumor volume was observed when VEGF suppression was started in 175-mm3 tumors. However, no growth inhibition was observed when VEGF suppression was started in 820-mm3 tumors. In these tumors, basic fibroblast growth factor and transforming growth factor α RNA expression was detected after VEGF was switched off. These findings demonstrate that VEGF is critical for the initial s.c. growth of T-47D breast carcinoma cells, whereas other angiogenic factors can compensate for the loss of VEGF after the tumors have reached a certain size.