Detailed knowledge of the mechanism of action of anti-cancer drugs is a requirement for the design of clinical trials tailored to their function. In our work conducted over the past 3 years, we have focused on understanding how tetrathiomolybdate, a copper lowering agent, inhibits tumor growth and angiogenesis. We surmised at the outset that since copper is involved in the secretion and function of several angiogenic factors, copper deficiency would have a fairly global, possibly general effect of inhibiting angiogenesis in tumors. Our work in breast cancer, prostate cancer, lung cancer, and squamous cell cancer provide important evidence in support of the global and generalizable effects of copper deficiency. Specifically, our previous work under this grant on in vitro and in vivo models of breast cancer has strongly implicated inhibition of NFkappaB activation by copper deficiency as a key causative event. Armed with a recent explosion of knowledge from many laboratories on the function of various components of the NFkappaB system, here we propose to define in detail how copper deficiency inhibits NFkappaB activation in cancer cells and in normal and tumor associated endothelial cells.
We aim to separate the inhibitory effects of copper deficiency on the secretion of key activators of NFkappaB, such as IL-1 from the intrinsic inhibition of NFkappaB activation and subsequent synthesis if target genes (TNF, IL-6, IL-8, lAP, MMPs). Our overarching, empirical hypothesis is that copper deficiency affects NFkappaB activation by altering the activation of transcription after the factors are localized to the nucleus. There are many steps in the process of activation of NFkappaB, from synthesis of the components to DNA binding and transcription activation where Cu could play a role. We also postulate that due to the growth arrest elicited by copper deficiency in bulky tumors, the inhibition of NFkappaB activity also extends to key mediators of tumor cell invasion, such as membrane type 1 matrix metalloproteases (MT1-MMPs). In this revised application, in addition, we consider the alternative hypotheses that Cu deficiency has effects on the AP-1 and SP-1 transcription factors, possibly mediated by alterations of erk signaling. In order to test these mechanistic hypotheses and continue to delineate the action of copper deficiency in detail, we propose the following specific aims: 1) Understand the signaling level at which copper deficiency interferes with TNFalpha and IL-1- induced NFkappaB activation in in vitro models of breast and other cancers and the effects of Cu deficiency on AP-1 and SP-1 transcription. 2) Delineate the interaction between NFkappaB activation and microtubular outgrowth in tumor conditioned endothelial cells. A) Investigate the copper dependence of the process whereby tumor cells elicit outgrowth of primordial vessels in endothelial cells exposed to a tumor-conditioned milieu; B) Separate the effects of decreased IL-1 secretion in a copper poor environment from the potential intrinsic inhibition of NFkappaB activation by copper deficiency. 3) Investigate the molecular surrogates of copper deficiency effects in incipient tumor and ductal hyperplastic and early tumor lesions in Her2/neu transgenic mice (high NFkappaB activity), wnt transgenic mice (normal NFkappaB activity). Define changes in expression of key mediators of the action of copper deficiency in the tumor lesions, the endothelium, and the stromal components. Understand whether TM regulates uPAR expression and erk signaling in her2 and wnt transgenic tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA077612-07
Application #
6949540
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Wolpert, Mary K
Project Start
1999-07-16
Project End
2008-06-30
Budget Start
2005-09-01
Budget End
2006-06-30
Support Year
7
Fiscal Year
2005
Total Cost
$362,537
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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