Journal Article

Effects of dietary daidzein and its metabolite, equol, at physiological concentrations on the growth of estrogen-dependent human breast cancer (MCF-7) tumors implanted in ovariectomized athymic mice

Young H. Ju, Jodi Fultz, Kimberly F. Allred, Daniel R. Doerge and William G. Helferich

in Carcinogenesis

Volume 27, issue 4, pages 856-863
Published in print April 2006 | ISSN: 0143-3334
Published online January 2006 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi320
Effects of dietary daidzein and its metabolite, equol, at physiological concentrations on the growth of estrogen-dependent human breast cancer (MCF-7) tumors implanted in ovariectomized athymic mice

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Genistein and daidzein are the main isoflavones in legumes. Equol is an intestinal bacterial metabolite of daidzein. In this study, we evaluated the estrogenic potential of daidzein and synthetic (±)-equol to stimulate growth of estrogen-dependent breast cancer (MCF-7) in vitro and in vivo. We hypothesize that estrogenic effects of daidzein and (±)-equol could modulate the growth of MCF-7 cells both in vitro and also once implanted into ovariectomized athymic mice. At concentrations between 0.001 and 50 μM, daidzein and (±)-equol stimulated the growth of MCF-7 cells with maximal stimulation at 1 μM in vitro. To evaluate their effects on the growth of MCF-7 cells implanted in ovariectomized athymic mice, two dietary dose–response studies [daidzein (125, 250, 500 and 1000 p.p.m.) and (±)-equol (250, 500 and 1000 p.p.m.)] were conducted. Tumor size and body weight were monitored weekly during the study. At completion of the study, we analyzed cellular proliferation of tumors using immunohistochemical staining (ki-67), pS2 expression in tumors using a real time quantitative reverse transcription–polymerase chain reaction (qRT–PCR), and total daidzein and (±)-equol levels in plasma using liquid chromatography–electrospray tandem mass spectrometry (LC–ES/MS/MS). Dietary daidzein had a slight but significant stimulatory effect on MCF-7 tumor growth in mice. No significant induction of pS2 mRNA (an estrogen-responsive marker) in tumors by dietary daidzein was observed. Total plasma daidzein concentrations in plasma were between 0.25 and 1.52 μM. Dietary equol treatment (for 37 weeks) did not stimulate MCF-7 tumor growth. There were no statistical differences in tumor size, proliferation and pS2 expression among any treatment groups. Total equol concentrations in plasma were 2.10–3.21 μM. In conclusion, daidzein and (±)-equol have proliferative effects on MCF-7 cell growth in vitro within the concentration range tested. Dietary daidzein had a slight but significant stimulatory effect on tumor growth, whereas (±)-equol did not stimulate the growth of estrogen-dependent breast tumor growth in athymic mice, increase the cell proliferation in tumors, or induce an estrogen-responsive pS2 expression. Total daidzein or (±)-equol plasma levels in mice fed the isoflavones were in the range that stimulated MCF-7 cell growth in vitro. These results suggest that pharmacokinetic and/or metabolic factors attenuate the estrogenic effects of daidzein and equol in vivo.

Keywords: AIN93G, American Institute of Nutrition 93 growth semi-purified diet; BCS, bovine calf serum; CD-BCS, charcoal-dextran stripped BCS; E2, 17β-estradiol; ER, estrogen receptor; LC-ES/MS–MS, liquid chromatography–electrospray/tandem mass spectrometry; MCF-7, Michigan Cancer Foundation-7; PBS, phosphate buffered saline; MEM, minimal essential media; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; OD, optical density; qRT–PCR, real time quantitative reverse transcription polymerase chain reaction; SEM, standard error of mean.

Journal Article.  6706 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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