Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04155 (pS2)
 1,234 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genistein, a component of soy products, may play a role in the prevention of breast and prostate cancer. However, little is known about the molecular mechanisms involved. In the present study, we examined the effects of genistein on the estrogen receptor positive human breast cancer cell line MCF-7. We observed that genistein stimulated estrogen-responsive pS2 mRNA expression at concentrations as low as 10(-8) M and these effects can be inhibited by tamoxifen. We also showed that genistein competed with [3H]estradiol binding to the estrogen receptor with 50% inhibition at 5 x 10(-7) M. Thus, the estrogenic effect of genistein would appear to be a result of an interaction with the estrogen receptor. The effect of genistein on growth of MCF-7 cells was also examined. Genistein produced a concentration-dependent effect on the growth of MCF-7 cells. At lower concentrations (10(-8)-10(-6) M) genistein stimulated growth, but at higher concentrations (> 10(-5) M) genistein inhibited growth. The effects of genistein on growth at lower concentrations appeared to be via the estrogen receptor pathway, while the effects at higher concentrations were independent of the estrogen receptor. We also found that genistein, though estrogenic, can interfere with the effects of estradiol. In addition, prolonged exposure to genistein resulted in a decrease in estrogen receptor mRNA level as well as a decreased response to stimulation by estradiol.
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PMID:Molecular effects of genistein on estrogen receptor mediated pathways. 862 49

Genistein, found in soy products, is a phytochemical with several biological activities. In the current study, our research focused on the estrogenic and proliferation-inducing activity of genistein. We have demonstrated that genistein enhanced the proliferation of estrogen-dependent human breast cancer (MCF-7) cells in vitro at concentrations as low as 10 nM, with a concentration of 100 nM achieving proliferative effects similar to those of 1 nM estradiol. Expression of the estrogen-responsive gene pS2 was also induced in MCF-7 cells in response to treatment with a concentration of genistein as low as 1 microM. At higher concentrations (above 20 microM), genistein inhibits MCF-7 cell growth. In vivo, we have shown that dietary treatment with genistein (750 ppm) for 5 days enhanced mammary gland growth in 28-day-old ovariectomized athymic mice, indicating that genistein acts as an estrogen in normal mammary tissue. To evaluate whether the estrogenic effects observed in vitro with MCF-7 cells could be reproduced in vivo, MCF-7 cells were implanted s.c. in ovariectomized athymic mice, and the growth of the estrogen-dependent tumors was measured weekly. Negative control animals received the American Institute of Nutrition (AIN)-93G diet, the positive control group received a new s.c. estradiol (2 mg) pellet plus the AIN-93G diet, and the third group received genistein at 750 ppm in the AIN-93G diet. Tumors were larger in the genistein (750 ppm)-treated group than they were in the negative control group, demonstrating that dietary genistein was able to enhance the growth of MCF-7 cell tumors in vivo. Increased uterine weights were also observed in the genistein-treated groups. In summary, genistein can act as an estrogen agonist in vivo and in vitro, resulting in the proliferation of cultured human breast cancer cells (MCF-7) and the induction of pS2 gene expression. Here we present new information that dietary genistein stimulates mammary gland growth and enhances the growth of MCF-7 cell tumors in ovariectomized athymic mice.
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PMID:Estrogenic effects of genistein on the growth of estrogen receptor-positive human breast cancer (MCF-7) cells in vitro and in vivo. 973 92

Genistein significantly inhibited cell growth (IC50 around 10 microM) of MCF-7, MDAMB-231 and HBL-100 cell lines, but not of skin-derived fibroblasts and counteracted the growth-stimulatory effects exerted by estradiol and growth factors. It abolished the paracrine stimulation observed in MCF-7 cells in co-culture with MDAMB-231 or fibroblasts. Genistein-treated cells accumulated in the S and G2/M phases of the cell cycle and underwent apoptosis. Genistein decreased tyrosine phosphorylation induced upon treatment with transforming growth factor-alpha. Finally, genistein bound the estrogen receptor (ER) (relative affinity constant Kd = 4 nM), induced pS2 and cathepsin-D transcription and increased nuclear ER levels.
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PMID:Genistein in the control of breast cancer cell growth: insights into the mechanism of action in vitro. 975 Dec 67

We compared the oestrogenic and anti-oestrogenic properties of the two well-known phyto-oestrogens, genistein and quercetin, on the oestrogen-sensitive breast cancer cell line MCF-7. Genistein exerted a biphasic effect on growth of MCF-7 cells, stimulating at low and inhibiting at high concentrations, whereas quercetin was only growth inhibitory. At doses which did not inhibit cell growth, respectively 5 and 1 microM, genistein and quercetin counteracted oestrogen- and transforming growth factor-alpha-promoted cell growth stimulation. Furthermore, genistein promoted transcription of the oestrogen-regulated genes pS2 and cathepsin-D, whereas quercetin interfered with the oestrogen-induced expression of the proteins. In in vitro binding experiments, genistein competed with oestradiol for binding to the oestrogen receptor (ER), but quercetin did not. Quercetin and genistein down-regulated cytoplasmic ER levels and promoted a tighter nuclear association of the ER, but only genistein was able to up-regulate progesterone receptor protein levels. In gel mobility assays, ER preincubation with oestradiol or with the two phyto-oestrogens led to the appearance of the same retarded band, excluding differences between the various complexes in binding to the consensus sequence. The data allowed us to conclude that quercetin acts like a pure anti-oestrogen, whereas genistein displays mixed agonist/antagonist properties, and to formulate a hypothesis on the possible mechanism of action of such phyto-oestrogens.
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PMID:The two phyto-oestrogens genistein and quercetin exert different effects on oestrogen receptor function. 1037 65

Genistein, a natural flavone found in soy has been postulated to be responsible for lowering the rate of breast cancer in Asian women. Our previous studies have shown that genistein exerts multiple suppressive effects on both estrogen receptor positive (ER+) as well as estrogen receptor negative (ER-) human breast carcinoma lines suggesting that the mechanisms of these effects may be independent of ER pathways. In the present study however we provide evidence that in the ER+ MCF-7, T47D and 549 lines but not in the ER-MDA-MB-231 and MDA-MB-468 lines both presumed "ER-dependent" and "ER-independent" actions of genistein are mediated through ER pathways. Genistein's antiproliferative effects are estrogen dependent in these ER+ lines, being more pronounced in estrogen-containing media and in the presence of exogenous 17-beta estradiol. Genistein also inhibits the expression of ER-downstream genes including pS2 and TGF-beta in these ER+ lines and this inhibition is also dependent on the presence of estrogen. Genistein inhibits estrogen-induced protein tyrosine kinase (PTK) activity. Genistein is only a weak transcriptional activator and actually decreases ERE-CAT levels induced by 17-beta estradiol in the ER+ lines. Genistein also decreases steady state ER mRNA only in the presence of estrogen in the ER+ lines thereby manifesting another suppression of and through the ER pathway. Our observations resurrect the hypothesis that genistein functions as a "good estrogen" in ER+ breast carcinomas. Since chemopreventive effects of genistein would be targeted to normal ER-positive ductal-lobular cells of the breast, this "good estrogen" action of genistein is most relevant to our understanding of chemoprevention.
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PMID:Genistein's "ER-dependent and independent" actions are mediated through ER pathways in ER-positive breast carcinoma cell lines. 1095 3

Epidemiologic and experimental studies support the hypothesis that dietary estrogens from plant sources (phytoestrogens) may play a role in the prevention of breast and prostate cancer. The molecular mechanisms for such chemopreventive effect are still unclear. We investigated the possibility that phytoestrogens may bind differentially to estrogen receptor proteins (ER[alpha] and ERss) and affect the interactions of the ligand-ER complexes with different estrogen response element (ERE) sequences. We used fluorescence polarization to measure the binding affinities of genistein, coumestrol, daidzein, glyceollin, and zearalenone for human ER[alpha] and ERss. Competition binding experiments revealed higher affinity of the phytoestrogens for ERss than for ER[alpha]. Genistein [median inhibitory concentration 12nM] is the most potent and has the same relative binding affinity for ERss as 17ss-estradiol. We also studied the effect of these phytoestrogens on the ability of ER[alpha] and ERss to associate with specific DNA sequences (EREs). The direct binding of human recombinant estrogen receptors to fluorescein-labeled EREs indicates that phytoestrogens can cause conformational changes in both human ERs, which results in altered affinities of the complexes for the ERE from the Xenopus vitellogenin A2 gene and an ERE from the human pS2 gene.
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PMID:Interactions of dietary estrogens with human estrogen receptors and the effect on estrogen receptor-estrogen response element complex formation. 1118 85

We have demonstrated that the isoflavone, genistein, stimulates growth of estrogen-dependent human breast cancer (MCF-7) cells in vivo (C. Y. Hsieh et al., Cancer Res., 58: 3833-3838, 1998). The isoflavones are a group of phytoestrogens that are present in high concentrations in soy. Whether consumption of genistein from soy protein will have similar effects on estrogen-dependent tumor growth as pure genistein has not been investigated in the athymic mouse tumor implant model. Depending on processing, soy protein isolates vary widely in concentrations of genistein. We hypothesize that soy isolates containing different concentrations of genistein will stimulate the growth of estrogen-dependent cells in vivo in a dose-dependent manner. To test this hypothesis we conducted experiments in which these soy protein isolates were fed to athymic mice implanted s.c. with estrogen-dependent tumors. Genistein content (aglycone equivalent) of the soy isolate diets were 15, 150, or 300 ppm. Positive (with 17beta-estradiol pellet implant) and negative (no 17beta-estradiol) control groups received casein-based (isoflavone-free) diets. Tumor size was measured weekly. At completion of the study animals were killed and tumors collected for evaluation of cellular proliferation and estrogen-dependent gene expression. Incorporation of bromodeoxyuridine into cellular DNA was used as an indicator of cell proliferation, and pS2 mRNA was used as an estrogen-responsive gene. Soy protein diets containing varying amounts of genistein increased estrogen-dependent tumor growth in a dose-dependent manner. Cell proliferation was greatest in tumors of animals given estrogen or dietary genistein (150 and 300 ppm). Expression of pS2 was increased in tumors from animals consuming dietary genistein (150 and 300 ppm). Here we present new information that soy protein isolates containing increasing concentrations of genistein stimulate the growth of estrogen-dependent breast cancer cells in vivo in a dose-dependent manner.
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PMID:Soy diets containing varying amounts of genistein stimulate growth of estrogen-dependent (MCF-7) tumors in a dose-dependent manner. 1143 39

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 microM, daidzein and (+/-)-equol stimulated the growth of MCF-7 cells with maximal stimulation at 1 muM 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 microM. 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 microM. 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.
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PMID: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. 1639 73

The objective of this work was to determine the interactive effects between soy bioactive components and tamoxifen (TAM) on prevention of estrogen-dependent breast cancer (BRCA). We initially investigated the effects of soy isoflavone genistein and TAM on the growth and cell cycle progression of estrogen-dependent MCF-7 human BRCA cells, and on the expression of ERalpha, pS2 and EGFR genes in vitro. Genistein or TAM alone inhibited the growth of MCF-7 cells in part via G(1) phase arrest, but their combinations showed suggestive antagonistic effects. We further evaluated the effects of bioactive soy components and TAM on the growth inhibition of MCF-7 tumors in a clinically relevant breast tumor model. TAM and bioactive soy components, genistein and soy phytochemical concentrate (SPC), delayed the growth of MCF-7 tumors. The combination of TAM with genistein or SPC, especially at the lower dose of TAM, had synergistic effects on delaying the growth of MCF-7 tumors. Biomarker determination suggests that the combination of TAM and soy components may synergistically delay the growth of MCF-7 tumors via their combined effects on induction of tumor cell apoptosis and inhibition of tumor cell proliferation. In addition, genistein and TAM combination synergistically delayed the growth of breast tumor via decreased estrogen level and activity, and down-regulation of EGFR expression. The results from our studies suggest that further investigations may be warranted to determine if the combination of TAM and bioactive soy components may be used for prevention and/or treatment of estrogen-dependent BRCA.
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PMID:Soy phytochemicals synergistically enhance the preventive effect of tamoxifen on the growth of estrogen-dependent human breast carcinoma in mice. 1723 21

Genistein (GEN), a soy isoflavone, stimulates growth of estrogen-dependent human tumor cells (MCF-7) in a preclinical mouse model for postmenopausal breast cancer. Antiestrogens and aromatase inhibitors are frontline therapies for estrogen-dependent breast cancer. We have demonstrated that dietary GEN can negate the inhibitory effect of tamoxifen. In this study, we evaluated the interaction of dietary GEN (at 250-1000 p.p.m. in the American Institute of Nutrition 93 growth diet) and an aromatase inhibitor, letrozole (LET), on the growth of tumors in an aromatase-expressing breast cancer xenograft model (MCF-7Ca) in the presence and absence of the substrate androstenedione (AD). Dietary GEN (250 and 500 p.p.m.) or implanted AD stimulated MCF-7Ca tumor growth. Implanted LET inhibited AD-stimulated MCF-7Ca tumor growth. In the presence of AD and LET, dietary GEN (250, 500 and 1000 p.p.m.) reversed the inhibitory effect of LET in a dose-dependent manner. Uterine wet weight, plasma estradiol (E(2)) levels (enzyme-linked immunosorbent assay) and total plasma GEN and LET levels (liquid chromatography-electrospray/tandem mass spectrometry) were measured. Ki-67 (cellular proliferation), aromatase and pS2 protein expression in tumors were evaluated using immunohistochemical (IHC) analysis. In conclusion, dietary GEN increased the growth of MCF-7Ca tumors implanted in ovariectomized mice and could also negate the inhibitory effect of LET on MCF-7Ca tumor growth. These findings are significant because tumors, which express aromatase and synthesize estrogen, are good candidates for aromatase therapy dietary and GEN can reverse the inhibitory effect of LET on tumor growth and adversely impact breast cancer therapy. Caution is warranted for consumption of dietary GEN by postmenopausal women with estrogen-dependent breast cancer taking LET treatment.
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PMID:Dietary genistein negates the inhibitory effect of letrozole on the growth of aromatase-expressing estrogen-dependent human breast cancer cells (MCF-7Ca) in vivo. 1863 54


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