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 because of 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 through 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-1alpha) protein expression and recruitment of HIF-1alpha to the hypoxia-response element in the VEGF promoter. In the mouse mammary gland, increased HEXIM1 expression decreased estrogen-driven VEGF and HIF-1alpha expression. Conversely, a mutation in the C-terminus of HEXIM1 (HEXIM1(1-312)) led to increased VEGF and HIF-1alpha expression and vascularization in mammary glands of heterozygous HEXIM1(1-312) mice when compared with their wild-type littermates. In addition, 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.
Ogba
N
N
Department of Pharmacology, Rainbow Babies and Children's Hospital, Cleveland, OH, USA.
Doughman
Y Q
YQ
Chaplin
L J
LJ
Hu
Y
Y
Gargesha
M
M
Watanabe
M
M
Montano
M M
MM
D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000378:metabolism; D018919:Neovascularization, Physiologic; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism*
D002273:Carcinogens; D047628:Estrogen Receptor alpha; C476123:HEXIM1 protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D004958:Estradiol; D042925:Positive Transcriptional Elongation Factor B
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