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File: Soy (Glycine max) Menopause Gene Expression HC 091121-433 Date: September 30, 2011 RE: Soy and Very Low Fat Diets Downregulate Gene Expression in Postmenopausal Women Wang J, Siegmund K, Tseng CC, Lee AS, Wu AH. Soy food supplementation, dietary fat reduction and peripheral blood gene expression in postmenopausal women - a randomized, controlled trial. Mol Nutr Food Res. 2011. doi:10.1002/mnfr.201100242. Both a soy (Glycine max) food diet and a low fat diet have been associated with lower breast cancer risk, but the benefit could not be explained by hormonal mechanisms. DNA microarray technology is used to study the effects of foods on cellular processes and therefore is a good tool to begin to elucidate potential mechanisms of action of these diets on cancer risk. The authors took advantage of a previously conducted, controlled dietary intervention study in healthy, postmenopausal women fed either a very low fat diet (VLFD), soy food diet, or control diet (CD), and performed gene expression profiling on their blood samples to investigate any differences. In the previously conducted study, the 59 participants were 1 year past their last menstrual period, not on any special diets, did not take hormone replacement therapy (HRT) 6 months prior, and had no history of cancer. They were randomized to either a VLFD (n=21; 11% of energy as fat), a Step 1 diet supplemented with soy food (SFD; n=20; 25% of energy as fat; 50 mg isoflavones per day), or a Step 1 CD alone (n=18; 27% energy as fat) for 8 weeks. Meals were provided daily by the Los Angeles County USC Medical Center Bionutrition Department's Research Kitchen and included breakfast, lunch, dinner, and a morning and evening snack. Caloric intake was adjusted semimonthly after weighing the participants in order to ensure no weight loss or gain > 2 kg; even so, there was a small but significant weight loss of 2-3 kg in all of the arms. Anthropometric, demographic, menstrual, reproductive, and menopausal data were collected at baseline. Body weight, blood pressure, and blood and urine samples were taken at baseline and every 2 weeks. Daily food logs and urinary isoflavone levels were used to monitor compliance. The authors obtained the baseline and 8-week blood samples from 58 of the participants and extracted total RNA for analysis in DNA microarrays.

The effects of the VLFD and SFD were similar in that both saw a pronounced downregulation of genes, but little upregulation. In contrast, the CD had a balanced upand downregulation pattern, but there were no significant differences between diet groups. Changes of gene subsets were noted by gene set enrichment analysis within diet groups. The VLFD and SFD both activated 3 particular pathways: "Chemokine signaling pathway," "Fc R-mediated phagocytosis," and "Natural killer cell-mediated cytotoxicity." Based on a < 0.8-fold downregulation change (and P < 0.05), the VLFD had 131 unique gene changes from its baseline, and the SFD had 66 unique gene changes from its baseline. This represents a fairly small number of changes, which may be related to the fact that the subjects were healthy and weight loss was small. For the SFD, the top 5 most downregulated genes in terms of fold change were DEFA1 (0.48fold, P=0.008), FCGR3B (0.52-fold, P=0.006), nicotinamide phosphoribosyltransferase (NAMPT) (0.55-fold, P=0.026), FCGR2A (0.61-fold, P=0.019), and prostaglandinendoperoxide synthase 2 (PTGS2) (0.63-fold, P=0.017). For the VLFD, the top 5 most downregulated genes were FCGR3B (0.49-fold, P=0.01), NAMPT (0.54-fold, P=0.027), FCGR2A (0.56-fold, P=0.005), BCL2A1 (0.57-fold, P=0.004), and ANXAs (0.58-fold, P=0.039). The NAMPT, FCGR3B, and FCGR2A genes showed the largest down-regulation in both diets. The NAMPT gene is associated with weight and insulin concentrations, and its increased expression in cancers is associated with poorer clinical outcomes. NAMPT, FCGR3B, and FCGR2A expressions are correlated in important ways to inflammatory pathways. However, more work will have to be done to determine whether the NAMPT and other gene expression modifications identified in this study were related to the dietary changes or were a secondary adaptive response. Risa Schulman, PhD
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