Molecular effects of genistein on estrogen receptor mediated pathways
Thomas T.Y. Wang, Neeraja Sathyamoorthy and James M. Phang
Laboratory of Nutritional and Molecular Regulation, NCI-Frederick Cancer Research and Development Center NIH, Frederick, MD 21702-1201, USA
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 produceda 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 (>10–5M) 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, thoughestrogenic, 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.
this is another excerpt
. However, due to the presence of the phenolic rings, and particularly the 4'-hydroxyl, they have the ability to bind to estrogen receptors, as do many substances, including antiestrogens like tamoxifen used successfully to treat breast cancer. Isoflavones show a higher relative affinity for binding to the ERß receptor, about six- to eightfold [63], and appear to model on selective estrogen receptor modulators (SERMs) in their conformational binding to the receptor [64]. Elegant X-ray crystallographic studies have probed and compared the conformational binding of estrogens [65], the recently approved SERM raloxifene (marketed in the USA by the name Evista), and the isoflavone genistein [66]. These studies show important and distinct differences in positioning of the compound within the dimerized ER-complex. Most striking is the position of several of the protein helices of the ER that are crucial in determining agonist or antagonist actions. The folding of helix-12 in particular governs the ability of the receptor complex to attract specific co-activator or co-repressor proteins [67,68] and this ultimately dictates the extent of agonist or antagonist actions [65]. In this regard, it has been shown that genistein sits in the ER-complex in a manner that is almost identical to that of raloxifene, and not like estradiol [66]. So, rather than classifying soy isoflavones as ‘estrogens,’ they should more correctly be judged to act hormonally as natural SERMs, as was recently suggested [69]. As such, this suggests that soy isoflavones are likely to have the beneficial effects of estrogen without the negatives, especially in tissues such as the endometrium and breast [64,70].
Just saying i've found I3C to be pretty good stuff, it is definitely one of those things not many know about that has great potential. The manner in which its dosed is crucial though.
