Angiogenesis, Metastasis, and the Cellular Microenvironment Control of VEGF Expression in Triple-Negative Breast Carcinoma Cells by Suppression of SAF-1 Transcription Factor Activity

Angiogenesis plays a significant role in cancer by providing increased blood supply to the affected tissues and thus bringing in growth factors, cytokines, and various nutrients for tumor growth. VEGF is the most prominent angiogenic agent that is markedly induced in cancer. Induction of VEGF has been widely studied but as cancer cells are quite adept at acquiring new alternative processes to circumvent surrounding environmental pressures, our understanding of the molecular mechanisms regulating VEGF expression in cancer, especially in triple-negative breast cancer cells, remains incomplete. Here, we present evidence of a novel mode of VEGF induction in triplenegative MDA-MB-231 breast cancer cells that is regulated by serum amyloid A activating factor 1 (SAF-1) transcription factor. Inhibition of SAF-1 by antisense short hairpin RNA profoundly reduces VEGF expression along with reduction in endothelial cell proliferation and migration. By both in vitro and in vivomolecular studies, we show that the effect of SAF-1 is mediated through its direct interaction with the VEGF promoter. In correlation, DNA-binding activity of SAF-1 is found to be significantly higher in MDA-MB-231 breast cancer cells. Examination of several breast cancer samples further revealed that SAF-1 is overexpressed in clinical breast cancer tissues. Taken together, these findings reveal that SAF-1 is a hitherto unrecognized participant in inducing VEGF expression in triple-negative breast cancer cells, an aggressive form of breast cancer that currently lacks effective treatment options. Suppression of SAF-1 activity in these cells can inhibit VEGF expression, providing a possible new method to control angiogenesis. Mol Cancer Res; 9(8); 1030–41. 2011 AACR.