HEXIM1 modulates vascular endothelial growth factor expression and function in breast epithelial cells and mammary gland

Recently, we found that mutation of the C-terminus of transcription factor Hexamethylene bisacetamide inducible protein 1 (HEXIM1) in mice leads to abnormalities in cardiovascular development due to aberrant vascular endothelial growth factor (VEGF) expression. HEXIM1 regulation of some genes has also been shown to be positive transcription elongation factor b (P-TEFb)-dependent. However, it is not known whether HEXIM1 regulates VEGF in the mammary gland. We demonstrate that HEXIM1 regulates estrogen-induced VEGF transcription via inhibition of Estrogen Receptor alpha recruitment to the VEGF promoter in a P-TEFb-independent manner in MCF-7 cells. Under hypoxic conditions, HEXIM1 inhibits estrogen-induced Hypoxia-inducible factor-1 alpha (HIF-1α) protein expression and recruitment of HIF-1α to the hypoxia response element in the VEGF promoter. In the mouse mammary gland, increased HEXIM1 expression decreased estrogen-driven VEGF and HIF-1α expression. Conversely, a mutation in the C-terminus of HEXIM1 (HEXIM1(1-312)) led to increased VEGF and HIF-1α expression and vascularization in mammary glands of heterozygous HEXIM1(1-312) mice when compared to their wild-type littermates. Additionally, HEXIM1(1-312) mice have a higher incidence of carcinogen-induced mammary tumors with increased vascularization, suggesting an inhibitory role for HEXIM1 during angiogenesis. Taken together, our data provide evidence to suggest a novel role for HEXIM1 in cancer progression.