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

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 17beta-estradiol (E2). 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, 32.1, 67.4 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 preclinical 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.

Intermolecular interactions identify ligand-selective activity of estrogen receptor α/β dimers

“…Phytoestrogens including genistein were originally thought to contribute to the decreased breast cancer risk associated with Asian women on high-soy diets compared with American women. However, recent animal, clinical, and gene expression studies provide evidence against its preventive role in breast cancer (32,33). Our BRET assay shows that genistein induces ER␣ homodimerization at 100 nM, a physiological concentration easily achievable by dietary intake (32)(33)(34)(35).…”

“…However, recent animal, clinical, and gene expression studies provide evidence against its preventive role in breast cancer (32,33). Our BRET assay shows that genistein induces ER␣ homodimerization at 100 nM, a physiological concentration easily achievable by dietary intake (32)(33)(34)(35). Because ER␤ expression is lost in highly aggressive tumors, the concomitant activity of genistein to induce ER␣ homodimerization and subsequently activate ER␣-mediated transcription (36) may explain the failure of genistein in clinical trails for the treatment of breast cancer.…”

Improvement of Bone Strength and Dermal Thickness Due to Dietary Edible Bird’s Nest Extract in Ovariectomized Rats

“…18) However, hyperdoses of isoflavones have been suggested to induce breast cancer. 19,20) It has been reported that circulating estrogen levels are positively associated with breast cancer risk. 21) In the present study, EBNE ingestion did not affect the serum estradiol concentration (Table 2).…”

Role of Metabolism in the Effects of Genistein and Its Phase II Conjugates on the Growth of Human Breast Cell Lines

“…Proposed anticancer mechanisms of action include modulation of estrogen receptor (ER) signaling as a partial agonist of ERα and β (6), downregulation of protein kinases and DNA topoisomerase (7), induction of early mammary cell differentiation (8), inhibition of angiogenesis (9), and modulation of intracellular enzyme activities (10). However, a few reports have shown that genistein can also increase proliferation of breast cancer cells in vitro and in ovariectomized rodent models of breast cancer (11)(12)(13)(14), suggesting the effects of genistein on the breast cancer cell growth may be multifaceted.…”