Suppression of NFkB by Tetrathiomolybdate Inhibits Tumor Angiogenesis and Enhances Apoptosis in Human Breast Cancers
Annual summary rept. 1 May 2002-30 Apr 2005
MICHIGAN UNIV ANN ARBOR
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Angiogenesis, the formation of capillaries from pre-existing blood vessels, is essential for sustained growth of solid tumors. Numerous studies have shown that copper is required to modulate several pro-angiogenic factors. However, the specific effects of copper homeostasis on tumor angiogenesis have not been extensively studies. Our preliminary studies demonstrated that tetrathiomolybdate, a potent and novel copper chelator, blocks tumor growth and angiogenesis. We hypothesize that TM is inhibiting tumor angiogenesis by decreasing levels of VEGF, bFGF, IL-6, and IL-8 through interference with the NFkB signaling cascade. In this proposal, the molecular mechanism whereby TM regulates NFkB expression and activity will be investigated. We will establish if the NFkB transcription factor complexes, p50, p52, RelA, and ReIB are regulated by TM using western blot analysis and gel shift assays. Furthermore, using a reporter gene system, we will ascertain if TM regulation of VEGF, bFGF, IL-6, and IL-8 is a direct consequence of NFkB signal inhibition. The studies as outlined will help us better understand the role of copper deficiency in tumor angiogenesis and may lead to a more specific and potent global anti-angiogenic approach to treat breast cancer.
- Anatomy and Physiology
- Medicine and Medical Research