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Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801 and
National Center for Toxicological Research, Jefferson, AR 72079
*
2To whom correspondence should be addressed. E-mail: helferic{at}uiuc.edu
ABSTRACT
Previously our laboratory has shown that the soy isoflavone, genistein,
stimulates growth of human breast cancer (MCF-7) cells in vivo and in
vitro. In this study, the dose-response analysis of genistein at
the physiologically achievable concentration range between 125 and
1,000 µg/g in the diet was conducted in ovariectomized
athymic nude mice implanted with MCF-7 cells. We hypothesized that
genistein at this concentration range can stimulate
dose-dependently the breast tumor growth, cell proliferation and an
estrogen-responsive pS2 gene induction. Tumor size and body weight
were monitored weekly. At completion of the study, we analyzed cellular
proliferation of tumors using incorporation of BrdU, pS2 expression of
tumors using a Northern blot analysis and total genistein level in
plasma using liquid chromatography–isotope dilution mass spectrometry
(LC-ES/MS). Dietary genistein (
250 µg/g) increased tumor
size in a dose-dependent manner [8.4x the negative control (NC)
group in the 250 µg/g group, 12.0x in the 500
µg/g group, 20.2x in the 1,000 µg/g group
and 23.2x in the positive control (PC) group]. The percentage of
proliferating cells was significantly increased by genistein at and
above 250 µg/g (5.3x the NC group in the 250
µg/g, 5.6x in the 500 µg/g, 5.0x in the
1,000 µg/g and 4.8x in the PC group). Expression
of pS2 mRNA was also significantly increased with increasing dietary
genistein levels (11.25x the NC group in the 500 µg/g
group and 15.84x in the 1,000 µg/g group). Total plasma
genistein concentrations were between 0.39 and 3.36 µmol/L
in mice fed between 125 and 1,000 µg/g genistein. In
conclusion, dietary treatment with genistein at physiological
concentrations produces blood levels of genistein sufficient to
stimulate 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.
KEY WORDS: • genistein • MCF-7 • athymic nude mouse • pS2 • BrdU
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