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Carcinogenesis Advance Access published online on March 14, 2006
Carcinogenesis, doi:10.1093/carcin/bgi370
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received August 26, 2005
Revised January 3, 2006
Accepted February 6, 2006

CARCINOGENESIS

Genistein stimulates growth of human breast cancer cells in a novel, postmenopausal animal model, with low plasma estradiol concentrations1

Young H. Ju 1, Kimberly F. Allred 2, Clinton D. Allred 2, and William G. Helferich 3 *

1 Department of Food Science and Human Nutrition, University of Illinois, 905 S Goodwin, Room 580 Bevier Hall, Urbana, IL; Current Address: 325 Wallace Hall Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic and State University, Blacksburg, Virginia 24061
2 Department of Food Science and Human Nutrition, University of Illinois, 905 S Goodwin, Room 580 Bevier Hall, Urbana, IL; Current Address: Department of Physiology, University of Kentucky, Lexington KY 40536
3 Department of Food Science and Human Nutrition, University of Illinois, 905 S Goodwin, Room 580 Bevier Hall, Urbana, IL

* To whom correspondence should be addressed.
William G. Helferich, E-mail: helferic{at}uiuc.edu


  Abstract

We have demonstrated that genistein (GEN) stimulates growth of estrogen-dependent breast tumors in vivo. In this study, we evaluated whether dietary GEN can act in an additive manner with low circulating levels of 17{beta}-estradiol (E2)5. We developed an E2 delivery system using silastic implants that yield low circulating plasma E2 levels similar to those observed in postmenopausal women. We inserted various concentrations of E2 silastic implants (1:127, 1:63, 1:31, 1:15, and 1:7 = E2:cholesterol) and injected estrogen-dependent human breast cancer (MCF-7) cells into ovariectomized athymic mice. The E2 implants tested (1:127 - 1:7) generated 30.1-101.6 pM E2 in plasma, which is comparable to the E2 levels observed in postmenopausal women. The E2 implants stimulated MCF-7 tumor growth in a dose dependent manner. We selected the 1:31 ratio of E2 implant to evaluate if dietary GEN acts in an additive manner with low E2 levels to influence the growth of MCF-7 tumors. Ovariectomized mice were divided into four groups: MCF-7 control, 500 ppm GEN, 1:31 E2, and 1:31 E2 + 500 ppm GEN. At week 17, the average tumor sizes were 7.6 mm2, 32.1 mm2, 67.4 mm2, and 106.8 mm2 for these groups, respectively (p<0.05), demonstrating that 500 ppm GEN additively stimulated MCF-7 tumor growth in the presence of low levels of E2. In summary, we established a pre-clinical mouse model that results in E2 blood concentrations similar to those found in postmenopausal women. Further, we observed that these concentrations regulate the growth rate of MCF-7 breast tumors. Using this model, we demonstrated that dietary GEN in the presence of low levels of circulating E2 act in an additive manner to stimulate estrogen-dependent tumor growth in vivo. Results from this study suggest that consumption of products containing GEN may not be safe for postmenopausal women with estrogen-dependent breast cancer.

Keywords: E2 silastic implant; genistein; MCF-7; athymic mouse; pS2; qRT-PCR; RIA.

1Supported by CA77355 and AG024387; Y.H.J. received postdoctoral support from the National Institutes of Environment, Health and Science Training Program Grant PHS T32 ES07326

5 AIN93G: American Institute of Nutrition 93 growth semi-purified diet, BCS: bovine calf serum, CD-BCS: charcoal-dextran stripped BCS, E2:17{beta}-estradiol, ER: estrogen receptor, MCF-7: Michigan Cancer Foundation-7, MEM: minimal essential media, qRT-PCR: reverse transcription polymerase chain reaction, RIA: radioimmunoassay, SEM: standard error of mean


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