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, angiogenesis and cell survival. We hyothesized that cancer cells subvert these normal hypoxia-dependent mechanisms to enable their own deregulated survival and growth. Our results indicate that loss of the p53 tumor suppressor gene augments HIF-1 and NF-kB-dependent transcriptional activation of the vascular endothelial growth factor (VEGF) gene and contributes to the an angiogenic switch during tumorigenesis. In addition, we find that activation of NF-kB by HER-2/neu- and 1GF-1 protects breast cancer cells from hypoxia- or death receptor-induced apoptosis. Conversely, repression of NF-kB by inhibition of IkB kinase (IKK) and casein kinase II (CK2) sensitizes breast cancer cells to hypoxia- or Apo2L/TRAIL-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. Accordingly, our results demonstrate that reduction of NF-kB- dependent survival proteins (by simultaneous inhibition of IKK and CK2) synergizes with interferon-gamma-mediated elevation of death signaling proteins to augment Apo2L/TRAIL-induced death of breast cancer cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2002
- Accession Number
- ADA410944
Entities
People
- Atul Bedi
Organizations
- Johns Hopkins University