Transcriptional Regulation of VEGF Expression in Breast Cancer

摘要

We had hypothesized that transcriptional regulation of Vascular Endothelial Growth Factor (VEGF) in breast cancer could be different from other types of cancer and tissues: an understanding of how the gene is regulated in this disease could be used as a baseline for developing improved treatment regimens. We have identified promoter elements and transcription factors that contribute to enhanced expression VEGF in breast cancer and other non-mammary cell lines. Under normoxic conditions a drop of > 40% in transcriptional activity could be observed in most cell lines when sequences upstream of the hypoxia-regulatory element (HRE) between positions -ll75 and -1010 were deleted. Sequences downstream of the HRE between positions -900 and -790 modulate promoter activity in a more cell type-specific manner; a further reduction in promoter activity by 30% was observed, while deletion of sequences between positions -790 and -700 restores promoter activity in some, but not all cell lines, indicating differences in transcriptional regulation among tissues and within the same cell type. Electrophoretic mobility shift assays (EMSA) identified hence to unknown potentially functional binding sites upstream of the HRE for transcription factors AP-l and Spl between positions -1125 and -1115, and -1098 and -1086, respectively.