Physiological concentrations of dietary genistein dose-dependently stimulate growth of estrogen-dependent human breast cancer (MCF-7) tumors implanted in athymic nude mice

Previously our laboratory has shown that the soy isoflavone, genistein, sti mulates growth of human breast cancer (MCF-7) cells in vivo and in vitro. I n this study, the dose-response analysis of genistein at the physiologicall y achievable concentration range between 125 and 1,000 mug/g in the diet wa s conducted in ovariectomized athymic nude mice implanted with MCF-7 cells. We hypothesized that genistein at this concentration range can stimulate d ose-dependently the breast tumor growth, cell proliferation and an estrogen -responsive pS2 gene induction. Tumor size and body weight were monitored w eekly. At completion of the study, we analyzed cellular proliferation of tu mors using incorporation of BrdU, pS2 expression of tumors using a Northern blot analysis and total genistein level in plasma using liquid chromatogra phy-isotope dilution mass spectrometry (LC-ES/MS). Dietary genistein (great er than or equal to 250 kg/g) increased tumor size in a dose-dependent mann er [8.4x the negative control (NC) group in the 250 mug/g group, 12.0x in t he 500 mug/g group, 20.2x in the 1,000 mug/g group and 23.2x in the positiv e control (PC) group]. The percentage of proliferating cells was significan tly increased by genistein at and above 250 mug/g (5.3x the NC group in the 250 mug/g, 5.6x in the 500 mug/g, 5.0x in the 1,000 mug/g and 4.8x in the PC group). Expression of pS2 mRNA was also significantly increased with inc reasing dietary genistein levels (11.25x the NC group in the 500 mug/g grou p and 15.84x in the 1,000 mug/g group). Total plasma genistein concentratio ns were between 0.39 and 3.36 mu mol/L in mice fed between 125 and 1,000 mu g/g genistein. In conclusion, dietary treatment with genistein at physiolog ical concentrations produces blood levels of genistein sufficient to stimul ate estrogenic effects, such as breast tumor growth, cellular proliferation and pS2 expression in athymic mice in a dose-responsive manner similar to that seen in vitro.