Accession Number:

ADA386866

Title:

Inhibition of Breast Cancer by Repression of Angiogenic Hypoxia-Inducible Transcription Factors

Descriptive Note:

Annual rept. 1 Sep 1999-31 Aug 2000

Corporate Author:

JOHNS HOPKINS UNIV BALTIMORE MD SCHOOLOF MEDICINE

Personal Author(s):

Report Date:

2000-09-01

Pagination or Media Count:

27.0

Abstract:

The key transcritional 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 hyothesize that cancer cells subvert vert these normal hypoxia-de pendent mechanisms to enable their own deregulated survival, neovasculogenesis, and growth. We propose that at inhibition of HIF-1 andor NF-kB can abrogate the angiogenic and apoptosis-resistant phenotype of breast tumors, thereby cuitailing their growth and metastases. We find that loss of the 53 tumor suppressor function promotes the neovascularization and growth of tumor xenografts. Our results indicate that PS inhibits NF-kB RelA activity via interaction with the 300 transcriptional integrator and promotes ubiquitin-mediated proteasomal degradation of the alpha subunit of HIF-1. Loss of p53 augments HIF-1 and NF-kB-dependent transcriptional activation of the vascular endothelial growth factor VEGF gene and contributes to the angiogenic switch during tumorigenesis. We are currently examining the effect of inhibiting HIF- 1 andor NF-kB on the growth, neovascularization, and metastatic potential of breast cancers in vitro and in vivo. The inhibition of breast cancers by repression of the key transcription factors governing adaptation to hypoxia, resistance to apoptosis, and angiogenesis could provide targets for innovative interventions to treat and prevent this disease.

Subject Categories:

  • Anatomy and Physiology
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE