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Molecular effects of genistein on estrogen receptor mediated pathways
T T Wang1, N Sathyamoorthy, J M Phang
1Laboratory of Nutritional and Molecular Regulation, NCI-Frederick Cancer Research and Development Center, NIH, MD 21702-1201, USA.
Abstract:
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.
Insights
Genistein, a soy isoflavone, acts as an estrogen by binding to the estrogen receptor, influencing breast cancer cell growth. However, high concentrations of genistein inhibit growth independently of the estrogen receptor.
Area of Science:
- Molecular Biology
- Cancer Research
- Nutritional Science
Background:
- Soy isoflavones, like genistein, are investigated for cancer prevention roles.
- The precise molecular mechanisms of genistein's action, particularly in breast cancer, remain incompletely understood.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying genistein's effects on estrogen receptor-positive human breast cancer cells (MCF-7).
- To investigate genistein's interaction with the estrogen receptor and its impact on cell proliferation.
Main Methods:
- Assessed genistein's effect on pS2 mRNA expression and [3H]estradiol binding to the estrogen receptor.
- Examined genistein's concentration-dependent impact on MCF-7 cell growth.
- Investigated the role of the estrogen receptor pathway in genistein's effects.
Main Results:
- Genistein demonstrated estrogenic activity, stimulating pS2 mRNA expression and binding to the estrogen receptor.
- Genistein exhibited a dual effect on cell growth: stimulation at low concentrations and inhibition at high concentrations.
- High-concentration genistein's anti-proliferative effect was independent of the estrogen receptor pathway.
Conclusions:
- Genistein exerts estrogenic effects via the estrogen receptor pathway.
- Genistein's impact on breast cancer cell growth is concentration-dependent and involves both estrogen receptor-dependent and -independent mechanisms.
- Prolonged genistein exposure may downregulate estrogen receptor mRNA levels and reduce cellular responsiveness to estradiol.