1.What major problem or issue is being resolved and how are you resolving it (summarize project aims and objectives)? How serious is the problem? What does it matter?
Prostate cancer is the most common cancer in American men: approximately 220,000 Americans are diagnosed with prostate cancer each year, and about 30,000 die each year from this disease. Despite the prevalence of this cancer and the great public interest in dietary treatments that might reduce the risk of cancer, basic research on the biochemical and genetic mechanisms underlying the relationship between nutrition and cancer is incomplete, fragmented, and often contradictory. If we can design evidence-based nutrient interventions that reduce the risk, prevent, or even delay the progression of prostate cancer we will increase the health and well-being of thousands of people, with the added benefit of decreasing medical costs for their treatment. Furthermore, prostate carcinoma is generally a confined, slowly progressing cancer whose progression can be monitored by a well known though non-specific diagnostic test (PSA). Unlike most cancers that are aggressively treated with medicines or surgery as soon as they are identified, early-stage prostate cancer is often simply observed and documented. Therefore, prostate cancer provides perhaps the ideal model for investigating the impact of nutrition-based treatments for reducing the risk of cancer progression, and thus our research on prostate cancer should provide important information for other more invasive cancers. This project seeks to identify the mechanisms by which micronutrients such as lycopene, selenium and zinc decrease the risk for prostate cancer progression in the United States.

We will focus on three objectives. 1) Identifying biochemical mechanisms of micronutrients such as lycopene, selenium, and zinc that influence prostate cancer progression, using normal and cancerous cell lines. 2) Testing these mechanisms and identifying new nutritionally influenced biomarkers of prostate cancer progression in animal models. 3) As time permits, testing the best combined intervention of micronutrients for its effectiveness against our newly identified and established putative biomarkers of prostate cancer in men with elevated risk for prostate cancer.

Our goal is to define the critical biochemical and genetic mechanisms that influence prostate cancer progression and its reduction by micronutrients. Completing this project will identify biomarkers and provide information on genetic and nutrient mechanisms that can be used to develop nutrient interventions that delay prostate cancer progression in the United States population.

2.List the milestones (indicators of progress) from your Project Plan.
Year 1 (FY 2005)

Begin studies of lycopene, selenium and zinc in normal and cancerous cell-lines

Develop study of genetic expression changes with prostate cancer progression in nude mice

Years 2 and 3 (FY 2006 and 2007)

Begin studies of zinc metabolism in knockout mice

Review results from single nutrient studies for zinc, selenium, and lycopene

Identify promising putative biomarkers and intermediate endpoints derived from cell-lines to test in mouse models

Statistical analysis and summary of gene expression data, identify most promising changes in gene expression for biomarker testing

Years 4 and 5 (FY 2008 and 2009)

Continue promising research in cell-lines, nude mice, and knockout mice

Develop and test promising putative biomarkers derived from cell-line and mouse model studies for use in humans, using a variety of single and combined nutrient interventions

Validate at least one promising nutritionally modified putative biomarker for prostate cancer

Begin one or more effective nutrient intervention studies in humans using mechanistic, genetic, and biomarker information derived from this research

Construct genetic map of genes that change reliably with prostate cancer progression and/or changes in micronutrient status

Identify genetic changes that can serve as putative biomarkers for prostate cancer progression reduction and for micronutrient deficiency and toxicity

Propose and text optimal micronutrient concentrations to be used for future clinical trials of micronutrient reduction of prostate cancer risk

4a.What was the single most significant accomplishment this past year?
Dr. Huang's research provides the first direct evidence for differences in zinc transporters in cancerous versus healthy prostatic cells. She found that cancerous cells accumulate lower levels of zinc compared to normal cells, and that cancerous cells had lower levels of some important zinc transporters, while other transporters were in the wrong location. This research could lead to improved understanding of how zinc in the diet is related to prostate cancer progression.

4b.List other significant accomplishments, if any.
Preliminary results suggest that Dr. Hawkes has identified a likely target of selenium chemoprevention in human prostate cells. Out of the 54,000 genes in the human genome, this selenium-containing protein of unknown function was derived from the gene whose expression was increased most by selenium. Similar genes are expressed in all phyla that have the molecular machinery for producing selenium-containing proteins and mice embryos with this gene deletion die after a couple of cell divisions. If these results are substantiated then this is an important discovery because this gene has the expected hallmarks of a gene whose function is intimately involved in regulating the fundamental biological processes leading to cancer.

4c.List any significant activities that support special target populations.
Dr. Huang is a co-PI for a USDA grant entitled "An evaluation of dietary zinc requirements for the elderly". The 3-year grant was funded on Dec. 1, 2004.

4d.Progress report.
None.

5.Describe the major accomplishments over the life of the project, including their predicted or actual impact.
None.

6.What science and/or technologies have been transferred and to whom? When is the science and/or technology likely to become available to the end-user (industry, farmer, other scientists)? What are the constraints, if known, to the adoption and durability of the technology products?
None.

7.List your most important publications in the popular press and presentations to organizations and articles written about your work. (NOTE: List your peer reviewed publications below).
Burri, B. J. Effect of antioxidant nutrients for the promotion of nutritional status of the elderly. In: 2004 Internat. Symposium – Nutritional approach for the health promotion of the elderly. Yeungnam University Press, Gyeongsan, South Korea. Pp 32-42. 2004.

Burri, B. J. and Clifford, A. J. Beta-carotene metabolism measured by accelerator mass spectrometry. Sight and Life Newsletter 1/2005:6-8. 2005.

Huang, L. Prostate zinc homeostasis and prostate carcinogenesis. Presentation to The NCMHD Center of Excellence for Nutritional Genomics Annual Retreat. 2005.

Huang, L. Does Zinc Fight Prostate Cancer? U.S. Dept. of Agriculture, Agricultural Research Service, News and Events. June 8, 2005

Huang, L. Unzipping Zinc’s Secrets. U.S. Dept. of Agriculture, Agricultural Research Service, Agricultural Research. 6:12-13, 2005.

Burri, B.J., Ishida, B.K., Chapman, M.H., Neidlinger, T.R. Lycopene isomer concentrations in blood after common red and tangerine tomato-based chili to healthy adult humans. American Chemical Society National Meeting.

Ishida, B.K., Burri, B.J., Chapman, M.H. Effects of processing on lycopene-isomer content of tangerine tomato. American Chemical Society National Meeting.

Burri, B.J., Clifford, A.J. Human carotenoid metabolism assessed with radioisotope techniques. International Vitamin A Consultative Group.

Review Publications
Wang, Z., Stoltenberg, M., Huang, L., Danscher, G., Dahlstrom, A., Shi, Y., Li, J. Abundant expression of zinc transporters in bergman glia of mouse cerebellum. Elsevier. Brian Res. Bulletin 64 (2005) 441-448.