NUTRITIONAL SCIENCES RESEARCH GROUP

Summary of Nutritional Science Awards - February 23, 2004

The following applications were approved for NCI awards and to be administered by the Division of Cancer Prevention Nutritional Science Research Group:

David J. Hunter, MBBS, SCD, Channing Laboratory, Epidemiology Center for Cancer Prevention, T: 617-525-2755; "Folate, 1-Carbon Nutrients, Gene Variants and Colon Cancer." The overall long-term goal is to establish the role of folate and other nutritional contributors to one-carbon metabolism in colorectal cancer by combining animal, mechanistic, human observational studies and clinical trials. A Cooperative Specialized Center will be established across several institutions (Harvard, Tufts, Dartmouth, the International Agency for Researcher in Cancer, University of Bergen in Europe, Variagenics Inc. and NCI). Data from several studies will be pooled to establish whether higher intake of folic acid reduces the risk of colorectal cancer and whether this reduced risk is greater for people with low methionine intake, low plasma folate, vitamins B12, B6, and B2 levels, consumers of more than one alcoholic beverage per day, and certain genetic variations. Mouse models for colon cancer will be validated. Data and samples from two randomized clinical trials looking at folate supplements to assess certain biomarkers for colon cancer risk.

Leena Hilakivi-Clarke, PhD, Lombardi Cancer Center, Department of Oncology, T: 202-687-7237; "Timing of Dietary Estrogenic Exposures and Breast Cancer Risk." The aim is to develop novel ways to prevent some sporadic and inherited breast cancers by dietary changes during pregnancy (for offspring and mother) and puberty. The timing of exposures to nutritional components that interact with steroid hormone receptors at the molecular level will be studied, particularly phytoestrogens, n-3 polyunsaturated fatty acids, selenium, obesity, and vitamins A and D. Associated mechanisms, such as changes in estrogen receptors and their signaling pathways, also will be investigated. Both animal models, including genetically modified mice, and human populations will be used. In humans, a special emphasis is given to women who are germline BRCA1 mutation carriers or pregnant. Through one of our cores, the center will further leverage significant existing studies (funded through NIH Innovative Molecular Analysis Technologies program, NIH Bioengineering Research Partnership program, and the Department of Defense Breast Cancer Research Program) that support the development, optimization, and application of innovative methods for the normalization, visualization, analysis/mining, and classification of very high dimensional genomic data. The investigators that are part of the center are located in Georgetown University, University Illinois at Urbana, Virginia Tech, Catholic University of America, and the Universities of Tampere and Turku in Finland, and the Karolinska Institutet in Sweden.

Stephen Barnes, PhD, University of Alabama, Birmingham, Department of Medicine, T: 205-934-7117; "Center for Nutrition-Gene Interaction in Cancer Prevention." This integrated effort will provide data on the roles of polyphenols and soy isoflavones in breast and prostate cancer, and of dietary soy on the first onset of menstruation. The focus is to identify genetic pathways that distinguish cancer cell development from normal cells, and how dietary polyphenols with documented chemopreventive activity impact these pathways. A combination of genomics, DNA microarray, and proteomic approaches will be used in cell culture and animal chemoprevention studies. These will be augmented by an epidemiological cohort study of primarily Asian girls who are soy and non-soy consumers to determine if this dietary component changes the timing of menarche, a risk factor for breast cancer. To accommodate the molecular approaches, part of the Center will focus on developing and evaluating new statistical procedures for analyzing the types of multidimensional data produced by current experimental approaches.

Leonard H. Augenlicht, PhD, Montefiore Medical Center, Department of Medical Oncology, T: 718-920-4663; "Molecular Nutrient Interaction in Intestinal Cancer." Technologies, including microarray analysis, novel transcriptional imaging methods, structural proteomics, global and locus specific gene methylation analysis, and laser capture microdissection, will be used to study how a Western style diet that mimics the major risk factors for colon cancer interacts with genetic factors to increase the likelihood of tumors forming in the intestinal tract. These risk factors include a diet high in fat and phosphate, low in calcium, vitamin D, choline, methionine, folate and fiber; a matrix of interactions among these dietary factors and genetic factors will be dissected. Focus will also be on the detailed mechanisms of regulation by genetic and dietary factors of key components of the cell cycle machinery and their interaction, both in tissue culture and in vivo. The experimental design encompasses complementary experiments in novel mouse genetic models of intestinal tumorigenesis, and in human subjects maintained in a General Clinical Research Unit, who will be fed diets in which components such as calcium and vitamin D are altered. For the human subjects, biopsies will be taken at various points to study the interaction of diet, intestinal cell changes, biomarkers and profiles of gene expression, and to make comparisons to mouse genetic models used in earlier phases of the project, as well as to existing gene expression data bases developed by this group that define cell maturation pathways in the intestine.

	NUTRITIONAL SCIENCES RESEARCH GROUP Summary of Nutritional Science Awards - February 23, 2004 The following applications were approved for NCI awards and to be administered by the Division of Cancer Prevention Nutritional Science Research Group: David J. Hunter, MBBS, SCD, Channing Laboratory, Epidemiology Center for Cancer Prevention, T: 617-525-2755; "Folate, 1-Carbon Nutrients, Gene Variants and Colon Cancer." The overall long-term goal is to establish the role of folate and other nutritional contributors to one-carbon metabolism in colorectal cancer by combining animal, mechanistic, human observational studies and clinical trials. A Cooperative Specialized Center will be established across several institutions (Harvard, Tufts, Dartmouth, the International Agency for Researcher in Cancer, University of Bergen in Europe, Variagenics Inc. and NCI). Data from several studies will be pooled to establish whether higher intake of folic acid reduces the risk of colorectal cancer and whether this reduced risk is greater for people with low methionine intake, low plasma folate, vitamins B12, B6, and B2 levels, consumers of more than one alcoholic beverage per day, and certain genetic variations. Mouse models for colon cancer will be validated. Data and samples from two randomized clinical trials looking at folate supplements to assess certain biomarkers for colon cancer risk. Leena Hilakivi-Clarke, PhD, Lombardi Cancer Center, Department of Oncology, T: 202-687-7237; "Timing of Dietary Estrogenic Exposures and Breast Cancer Risk." The aim is to develop novel ways to prevent some sporadic and inherited breast cancers by dietary changes during pregnancy (for offspring and mother) and puberty. The timing of exposures to nutritional components that interact with steroid hormone receptors at the molecular level will be studied, particularly phytoestrogens, n-3 polyunsaturated fatty acids, selenium, obesity, and vitamins A and D. Associated mechanisms, such as changes in estrogen receptors and their signaling pathways, also will be investigated. Both animal models, including genetically modified mice, and human populations will be used. In humans, a special emphasis is given to women who are germline BRCA1 mutation carriers or pregnant. Through one of our cores, the center will further leverage significant existing studies (funded through NIH Innovative Molecular Analysis Technologies program, NIH Bioengineering Research Partnership program, and the Department of Defense Breast Cancer Research Program) that support the development, optimization, and application of innovative methods for the normalization, visualization, analysis/mining, and classification of very high dimensional genomic data. The investigators that are part of the center are located in Georgetown University, University Illinois at Urbana, Virginia Tech, Catholic University of America, and the Universities of Tampere and Turku in Finland, and the Karolinska Institutet in Sweden. Stephen Barnes, PhD, University of Alabama, Birmingham, Department of Medicine, T: 205-934-7117; "Center for Nutrition-Gene Interaction in Cancer Prevention." This integrated effort will provide data on the roles of polyphenols and soy isoflavones in breast and prostate cancer, and of dietary soy on the first onset of menstruation. The focus is to identify genetic pathways that distinguish cancer cell development from normal cells, and how dietary polyphenols with documented chemopreventive activity impact these pathways. A combination of genomics, DNA microarray, and proteomic approaches will be used in cell culture and animal chemoprevention studies. These will be augmented by an epidemiological cohort study of primarily Asian girls who are soy and non-soy consumers to determine if this dietary component changes the timing of menarche, a risk factor for breast cancer. To accommodate the molecular approaches, part of the Center will focus on developing and evaluating new statistical procedures for analyzing the types of multidimensional data produced by current experimental approaches. Leonard H. Augenlicht, PhD, Montefiore Medical Center, Department of Medical Oncology, T: 718-920-4663; "Molecular Nutrient Interaction in Intestinal Cancer." Technologies, including microarray analysis, novel transcriptional imaging methods, structural proteomics, global and locus specific gene methylation analysis, and laser capture microdissection, will be used to study how a Western style diet that mimics the major risk factors for colon cancer interacts with genetic factors to increase the likelihood of tumors forming in the intestinal tract. These risk factors include a diet high in fat and phosphate, low in calcium, vitamin D, choline, methionine, folate and fiber; a matrix of interactions among these dietary factors and genetic factors will be dissected. Focus will also be on the detailed mechanisms of regulation by genetic and dietary factors of key components of the cell cycle machinery and their interaction, both in tissue culture and in vivo. The experimental design encompasses complementary experiments in novel mouse genetic models of intestinal tumorigenesis, and in human subjects maintained in a General Clinical Research Unit, who will be fed diets in which components such as calcium and vitamin D are altered. For the human subjects, biopsies will be taken at various points to study the interaction of diet, intestinal cell changes, biomarkers and profiles of gene expression, and to make comparisons to mouse genetic models used in earlier phases of the project, as well as to existing gene expression data bases developed by this group that define cell maturation pathways in the intestine.



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