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Carcinogenesis Advance Access published online on July 16, 2008
Carcinogenesis, doi:10.1093/carcin/bgn161
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Dietary Genistein Negates the Inhibitory Effect of Letrozole On The Growth Of Aromatase-expressing Estrogen-Dependent Human Breast Cancer Cells (MCF-7Ca) In Vivo

Young H. Ju1,2,4, Daniel R. Doerge3, Kellie A. Woodling3, James A. Hartman1, Jieun Kwak2 and William G. Helferich1,4

1 Department of Food Science and Human Nutrition, University of Illinois, 905 S Goodwin, Room 580 Bevier Hall, Urbana, IL
2 Current Address: 325 Wallace Hall Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic and State University, Blacksburg, Virginia 24061
3 National Center for Toxicological Research, Jefferson, Arkansas 72079

4 Corresponding authors: William Helferich, Department of Food Science and Human Nutrition, University of Illinois, 905 S. Goodwin, Room 580 Bevier Hall, Urbana, IL Voice: 217-244-5414 or helferic{at}uiuc.edu, and Young Ju, Department of Human Nutrition, Foods and Exercise, Virginia Tech, 325 Wallace Hall, Blacksburg, VA Voice: 540-231-6168 or yhju{at}vt.edu

Genistein (GEN), a soy isoflavone, stimulates growth of estrogen-dependent human tumor cells (MCF-7) in a preclinical mouse model for post-menopausal breast cancer. Anti-estrogens and aromatase inhibitors are front-line therapies for estrogen-dependent breast cancer. We have demonstrated that dietary GEN can negate the inhibitory effect of tamoxifen. In this study we evaluated the interaction of dietary GEN (at 250 - 1000 ppm in the AIN93G diet) and an aromatase inhibitor, Letrozole (LET), on the growth of tumors in an aromatase-expressing breast cancer xenograft model (MCF-7Ca) in the presence and absence of the substrate androstenedione (AD). Dietary GEN (250 and 500 ppm) or implanted AD stimulated MCF-7Ca tumor growth. Implanted LET inhibited AD-stimulated MCF-7Ca tumor growth. In the presence of AD and LET, dietary GEN (250, 500, and 1000 ppm) reversed the inhibitory effect of LET in a dose-dependent manner. Uterine wet weight, plasma estradiol (E2) levels (ELISA), and total plasma GEN and LET levels (LC-ES-MS/MS) were measured. Ki-67 (cellular proliferation), aromatase, and pS2 protein expression in tumors was evaluated using immunohistochemical (IHC) analysis. In conclusion, dietary GEN increased the growth of MCF-7Ca tumors implanted in ovariectomized mice and could also negate the inhibitory effect of LET on MCF-7Ca tumor growth. These findings are significant because tumors, which express aromatase and synthesize estrogen, are good candidates for aromatase therapy, dietary? GEN can reverse the inhibitory effect of LET on tumor growth and adversely impact breast cancer therapy. Caution is warranted for consumption of dietary GEN by postmenopausal women with estrogen-dependent breast cancer taking LET treatment.

Received November 12, 2007; revised June 23, 2008; accepted June 28, 2008.


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