Accession Number:

ADA495898

Title:

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

Descriptive Note:

Final rept. 1 Sep 1999-31 Aug 2003

Corporate Author:

JOHNS HOPKINS UNIV BALTIMORE MD SCHOOL OF MEDICINE

Personal Author(s):

Report Date:

2003-09-01

Pagination or Media Count:

27.0

Abstract:

The clonal evolution of tumor cells in hypoxic microenvironments ultimately selects subpopulations that not only resist apoptosis, but also promote angiogenesis. The transcriptional regulators of the normal hypoxic response, Hypoxia Inducible Factor-I HIF-I and NF-KB, are responsible for induction of genes that promote anaerobic metabolism, cell survival, vasodilatation, and angiogenesis. We hypothesize that cancer cells subvert these normal hypoxia-dependent mechanisms to enable their own deregulated survival, neovasculogenesis, and growth. We propose that inhibition of HIF-I andor NF-KB can abrogate the angiogenic and apoptosis-resistant phenotype of breast tumors, thereby curtailing their growth and metastases. We aim to elucidate the molecular mechanisms by which the p53 tumor suppressor regulates HIF-land NF-KB activity and examine the effect of inhibiting HIF-I andor NF-kB on the growth, neovascularization, and metastatic potential of breast cancers in vitro and in vivo. These studies will provide insights into the molecular mechanisms governing the response to hypoxic stress and will determine whether their subversion by breast cancers is responsible for their apoptosis-resistant and angiogenic phenotype. These key transcription factors could provide target for innovative interventions for the treatment and prevention of breast cancer.

Subject Categories:

  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE