Berries and Ellagic Acid Prevent Estrogen-Induced Mammary Tumorigenesis by Modulating Enzymes of Estrogen Metabolism

To determine whether dietary berries and ellagic acid prevent 17 beta-estradiol (E-2)-induced mammary tumors by altering estrogen metabolism, we randomized August-Copenhagen Irish rats (n = 6 per group) into five groups: sham implant + control diet, E-2 implant + control diet (E-2-CD), E-2 + 2.5% black raspberry (E-2-BRB), E-2 + 2.5% blueberry (E-2-BB), and E-2 + 400 ppm ellagic acid (E-2-EA). Animals were euthanized at early (6 wk), intermediate (18 wk), and late (24 wk) phases of E-2 carcinogenesis, and the mammary tissue was analyzed for gene expression changes using quantitative real-time PCR. At 6 weeks, E-2 treatment caused a 48-fold increase in cytochrome P450 1A1 (CYP1A1; P < 0.0001), which was attenuated by both BRB and BB diets to 12- and 21-fold, respectively (P < 0.001). E-2 did not alter CYP1B1 levels, but both berry and EA diets significantly suppressed it by 11- and 3.5-fold, respectively, from baseline (P < 0.05). There was a 5-fold increase in 17 beta-hydroxysteroid dehydrogenase 7 (17 beta HSD7), and this was moderately abrogated to similar to 2-fold by all supplementation (P < 0.05). At 18 weeks, CYP1A1 was elevated by 15-fold in E-2-CD and only E-2-BB reduced this increase to 7-fold (P < 0.05). Catechol-O-methyltransferase expression was elevated 2-fold by E-2 treatment (P < 0.05), and all supplementation reversed this. At 24 weeks, CYP1A1 expression was less pronounced but still high (8-fold) in E-2-treated rats. This increase was reduced to 3.2- and 4.6-fold by E-2-BRB and E-2-EA, respectively (P < 0.05), but not by E-2-BB. Supplementation did not alter the effect of E-2 on steroid receptors. The diets also significantly suppressed mammary tumor incidence (10-30%), volume (41-67%), and multiplicity (38-51%; P < 0.05). Berries may prevent mammary tumors by suppressing the levels of E-2-metabolizing enzymes during the early phase of E-2 carcinogenesis. Cancer Prev Res; 3(6); 727-37. (C) 2010 AACR.