In the US, breast cancer is a serious health problem for women; approximately one out of every nine will develop breast cancer during her life, especially postmenopausal women. Evidence has indicated that breast cancer risk may be decreased by dietary fat reduction and increased intake of fruits & vegetables. The efficacies of these two dietary factors are currently being investigated in two nationwide clinical trials, i.e. the Women's Health Initiative (WHI) and the Women's Intervention Nutrition Study (WINS). Clinical trials, using cancer incidence or mortality as endpoints, usually require a lengthy duration, large subject populations and huge costs to achieve statistical significance; these limitations can be circumvented if suitable biomarkers reflecting intermediate endpoints can be identified. The goal of our proposed research is to identify and validate putative biomarkers that can be used accurately, quickly, and efficiently to monitor the clinical activity of intervention agents and to identify high risk subjects. Since DNA base-modifications as a result of oxidation and hypomethylation have been suggested to be associated with the development of cancers, our hypothesis is that intervention with dietary fat reduction and increased intake of fruits & vegetables can decrease the DNA base-modifications, and hence reduce breast cancer risk. Three putative biomarkers of DNA base-modifications, namely 8-hydroxy-2'- deoxyguanosine, 5-methyl-2'-deoxycytidine and malondialdehyde, in three easily accessible human specimens--buccal mucosal cells, peripheral white blood cells and urine--will be evaluated. A total of 45 postmenopausal women between the ages of 50 to 65 years and of all ethnic backgrounds will be recruited in 3 years for the proposed pilot study which will be carried out in three cycles, 15 subjects per cycle. Each cycle will consist of a 2-month run-in period and a 6-month dietary intervention period. After the run-in, the subjects will be randomly assigned into three groups: control, low-fat, and low fat+high-fruits & vegetables. The intervention will reduce fat intake from >30% to 15% of total calories and increase the intake of fruits and vegetables from 1-2 servings to > 5 servings per day. The data obtained will be used to determine: 1) the baseline values and the intra- and inter-individual variation of the biomarkers; 2) the relationship between the levels of biomarkers and fat intake, plasma micronutrients, red blood cell folate, serum estrogen and serum lipids; and 3) whether or not the biomarkers are able to be modulated by the intervention agents. When the pilot study is successfully accomplished, a new grant will be requested to carry out an expanded clinical trial in conjunction with the WHI and the WINS to determine whether or not the modulation of the biomarkers by the intervention agents is associated with a reduced risk of human breast and other cancers.
