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

Oncogene volume 29, pages 3639–3649 (2010)Cite this article

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Abstract

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-α 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 (HEXIM11−312) led to increased VEGF and HIF-1α expression and vascularization in mammary glands of heterozygous HEXIM11−312 mice when compared with their wild-type littermates. In addition, HEXIM11−312 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.

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Acknowledgements

We thank Drs Anthony J Berdis and Jay Prendergast for reagents and their help with kinase and ELISA assays. This work was supported by the National Institute of Health Grant CA92440 and the American Heart Association Grant to MMM and a Department of Defense predoctoral Fellowship W81XWH-06-1-0426 to NO.

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Authors and Affiliations

  1. Department of Pharmacology, Rainbow Babies and Children's Hospital, Cleveland, OH, USA

    N Ogba, L J Chaplin, Y Hu & M M Montano

  2. Department of Pediatrics, Rainbow Babies and Children's Hospital, Cleveland, OH, USA

    Y Q Doughman & M Watanabe

  3. Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA

    M Gargesha

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  1. N Ogba
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  2. Y Q Doughman
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Correspondence to M M Montano.

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Ogba, N., Doughman, Y., Chaplin, L. et al. HEXIM1 modulates vascular endothelial growth factor expression and function in breast epithelial cells and mammary gland. Oncogene 29, 3639–3649 (2010). https://doi.org/10.1038/onc.2010.110

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