Inhibition of Breast Cancer by Repression of Angiogenic Hypoxia-Inducible Transcription Factors
Abstract
The key transcriptional regulators of the cellular hypoxic response, Hypoxia Inducible Factor-1 (HIF-1) and NF-kB, are responsible for induction of genes that regulate anaerobic metabolism, cell survival, and angiogenesis. We hypothesize that cancer cells subvert these normal hypoxia-dependent mechanisms to enable their own deregulated survival, neovasculogenesis, and growth. We find that loss of the p53 tumor suppressor gene promotes the neovascularization and growth of tumor xenografts. Our results indicate that p53 inhibits NF-kB RelA activity via interaction with the p300 transcriptional integrator and promotes ubiquitin-mediated proteasomal degradation of the alpha subunit of HIF-l. Loss of p53 augments HIF-1- and NK-kB-dependent transcriptional activation of the vascular endothelial growth factor (VEGF) gene and contributes to the angiogenic switch during tumorigenesis. In addition, we find that activation of NF-kB by HER-2/neu- and IGF-1 protects breast cancer cells from hypoxia- or death receptor-induced apoptosis. Conversely, repression of NF-kB inhibition of the 1kB kinase-NEMO complex sensitizes breast cancer cells to hypoxia- or TRAIL/Apo21 induced death. Together, our studies indicate that the constitutive activation of HIF-1 and NF-kB in breast cancers may underlie their angiogenic and apoptosis-resistant phenotype; as such, these transcription factors could provide attractive targets for innovative interventions to treat and prevent human breast cancers.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2001
- Accession Number
- ADA403394
Entities
People
- Atul Bedi
Organizations
- Johns Hopkins University