1α,25‐dihydroxyvitamin D regulates vascular endothelial growth factor and hypoxia‐inducible factor‐1α in breast epithelial cells

Abstract

The angiogenic vascular endothelial growth factor (VEGF) has been shown to be differentially regulated by 1α, 25‐dihydroxyvitamin D (1,25(OH)2D) in untransformed cells and cancer cells, but the effect at different stages of cancer progression has not been investigated in breast epithelial cells. Evidence also suggests that 1,25(OH)2D reduces VEGF expression through stabilization of hypoxia‐inducible factor (HIF)‐1α, a direct transcriptional regulator of VEGF. The purpose of this study was to determine the impact of 1,25(OH)2D on VEGF expression in untransformed and H‐ras transfected MCF10A breast epithelial cells. Compared to vehicle, 1,25(OH)2D treatment (24 hrs) significantly reduced VEGF mRNA expression in a dose‐dependent manner, with significance achieved at 1 nM (25%) in untransformed cells. Similarly, with 1,25(OH)2D (1 nM) treatment, mRNA expression of HIF‐1α was also significantly decreased by 32% compared to vehicle in untransformed cells. In ras‐transfected MCF10A cells, 1,25(OH)2D‐mediated reduction of VEGF (28%) and HIF‐1α (34%) mRNA was achieved only at a higher dose (10 nM and 100nM, respectively) compared to vehicle. These results suggest that in breast cells, 1,25(OH)2D‐induced suppression of VEGF may occur through the transcriptional regulation of HIF‐1α, and the effect may be reduced in the presence of the H‐ras oncogene. Supported by NIH DK069965.