p16 Modulates VEGF Expression via Its Interaction With HIF-1α in Breast Cancer Cells

The degree of tumor progression (such as growth, angiogenesis, and metastasis) directly correlates with the expression of vascular endothelial growth factor (VEGF), but inversely correlates with the expression of tumor-suppressor gene p16, therefore we examined whether the restoration of p16 in breast cancer cells would modulate VEGF expression. Adenoviral-mediated p16 expression downregulated VEGF gene expression in breast cancer cells, and inhibited breast cancer cell-induced angiogenesis by a dorsal air sac model in mice. Moreover, p16 appears to form a complex with HIF-1 alpha, the transcription factor for the VEGF gene promoter. Taken together, the binding between p16 and HIF-1a protein may alter HIF-1 alpha's ability to transactivate VEGF expression.