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

<jats:title>Abstract</jats:title> <jats:p>To determine whether dietary berries and ellagic acid prevent 17β-estradiol (E2)–induced mammary tumors by altering estrogen metabolism, we randomized August-Copenhagen Irish rats (n = 6 per group) into five groups: sham implant + control diet, E2 implant + control diet (E2-CD), E2 + 2.5% black raspberry (E2-BRB), E2 + 2.5% blueberry (E2-BB), and E2 + 400 ppm ellagic acid (E2-EA). Animals were euthanized at early (6 wk), intermediate (18 wk), and late (24 wk) phases of E2 carcinogenesis, and the mammary tissue was analyzed for gene expression changes using quantitative real-time PCR. At 6 weeks, E2 treatment caused a 48-fold increase in cytochrome P450 1A1 (CYP1A1; P &lt; 0.0001), which was attenuated by both BRB and BB diets to 12- and 21-fold, respectively (P &lt; 0.001). E2 did not alter CYP1B1 levels, but both berry and EA diets significantly suppressed it by 11- and 3.5-fold, respectively, from baseline (P &lt; 0.05). There was a 5-fold increase in 17β-hydroxysteroid dehydrogenase 7 (17βHSD7), and this was moderately abrogated to ∼2-fold by all supplementation (P &lt; 0.05). At 18 weeks, CYP1A1 was elevated by 15-fold in E2-CD and only E2-BB reduced this increase to 7-fold (P &lt; 0.05). Catechol-O-methyltransferase expression was elevated 2-fold by E2 treatment (P &lt; 0.05), and all supplementation reversed this. At 24 weeks, CYP1A1 expression was less pronounced but still high (8-fold) in E2-treated rats. This increase was reduced to 3.2- and 4.6-fold by E2-BRB and E2-EA, respectively (P &lt; 0.05), but not by E2-BB. Supplementation did not alter the effect of E2 on steroid receptors. The diets also significantly suppressed mammary tumor incidence (10-30%), volume (41-67%), and multiplicity (38-51%; P &lt; 0.05). Berries may prevent mammary tumors by suppressing the levels of E2-metabolizing enzymes during the early phase of E2 carcinogenesis. Cancer Prev Res; 3(6); 727–37. ©2010 AACR.</jats:p>