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

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 17β-estradiol (E 2 ). We developed an E 2 delivery system using silastic implants that yield low circulating plasma E 2 levels similar to those observed in postmenopausal women. We inserted various concentrations of E 2 silastic implants (1:127, 1:63, 1:31, 1:15 and 1:7 = E 2 :cholesterol) and injected estrogen-dependent human breast cancer (MCF-7) cells into ovariectomized athymic mice. The E 2 implants tested (1:127-1:7) generated 30.1-101.6 pM E 2 in plasma, which is comparable to the E 2 levels observed in postmenopausal women. The E 2 implants stimulated MCF-7 tumor growth in a dose-dependent manner. We selected the 1:31 ratio of E 2 implant to evaluate if dietary GEN acts in an additive manner with low E 2 levels to influence the growth of MCF-7 tumors. Ovariectomized mice were divided into four groups: MCF-7 control, 500 ppm GEN, 1:31 E 2 , and 1:31 E 2 + 500 ppm GEN. At week 17, the average tumor sizes were 7.6, 32.1, 67.4 and 106.8 mm 2 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 E 2 . In summary, we established a preclinical mouse model that results in E 2 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 E 2 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.