ER BETA

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    ER BETA


    Doc,

    From everything I've read ER beta plays a protective role in many areas of the body, yet you mention in another thread that its is important to down regulate ER beta in addition to ER aplha. Certain products (i.e. I3C, Episatne, etc.) atcually target ER beta receptors while leaving ER alpha unchanged. Your comments would be appreciated.

    Estrogen receptor beta (ERbeta) plays a protective role against uncontrolled cell proliferation. ERbeta is lost during prostate cancer (CaP) progression suggesting its direct involvement in contrasting tumor proliferation in this disease; however, the molecular mechanism at the basis of this effect has not been clearly defined yet. Possible molecular targets of ERbeta were assessed in DU145 cells, a CaP cell line expressing only ERbeta. Cells treated from 1 to 9 days with different doses of estradiol or diarylpropionitrile (DPN, an ERbeta-selective agonist) show a time-dependent decrease in cell proliferation. The reduced proliferation rate is accompanied by the stimulation of ERbeta expression and the increase of cyclin-dependent kinase inhibitor p21. We demonstrate that the endogenous ERbeta is one of the mediator of the antiproliferative action of estrogens enhancing the synthesis of molecules such as p21 that control cell cycle, an effect amplified by the autoregulation of ERbeta expression. Our observations suggest that CaP, when expressing a functional ERbeta, might be sensitive to the antiproliferative action of estrogens; therefore, ERbeta specific agonists might be valid candidates for new pharmacological approaches to this disease.or beta polymorphism is associated with prostate cancer risk.

    Thellenberg-Karlsson C, Lindström S, Malmer B, Wiklund F, Augustsson-Bälter K, Adami HO, Stattin P, Nilsson M, Dahlman-Wright K, Gustafsson JA, Grönberg H.

    Department of Radiation Sciences/Oncology, University of Umeå, Umeå, Sweden.

    Abstract
    PURPOSE: After cloning of the second estrogen receptor, estrogen receptor beta (ERbeta) in 1996, increasing evidence of its importance in prostate cancer development has been obtained. ERbeta is thought to exert an antiproliferative and proapoptotic effect. We examined whether sequence variants in the ERbeta gene are associated with prostate cancer risk. EXPERIMENTAL DESIGN: We conducted a large population-based case-control study (CAncer Prostate in Sweden, CAPS) consisting of 1,415 incident cases of prostate cancer and 801 controls. We evaluated 28 single nucleotide polymorphisms (SNP) spanning the entire ERbeta gene from the promoter to the 3'-untranslated region in 94 subjects of the control group. From this, we constructed gene-specific haplotypes and selected four haplotype-tagging SNPs (htSNP: rs2987983, rs1887994, rs1256040, and rs1256062). These four htSNPs were then genotyped in the total study population of 2,216 subjects. RESULTS: There was a statistically significant difference in allele frequency between cases and controls for one of the typed htSNPs (rs2987983), 27% in cases and 24% in controls (P = 0.03). Unconditional logistics regression showed an odds ratio of 1.22 (95% confidence interval, 1.02-1.46) for men carrying the variant allele TC or CC versus the wild-type TT, and an odds ratio of 1.33 (95% confidence interval, 1.08-1.64) for localized cancer. No association of prostate cancer risk with any of the other SNPs or with any haplotypes were seen. CONCLUSION: We found an association with a SNP located in the promoter region of the ERbeta gene and risk of developing prostate cancer. The biological significance of this finding is unclear, but it supports the hypothesis that sequence variation in the promoter region of ERbeta is of importance for risk of prostate cancer.


    I keep finding more and more evidence that Er beta has a protective role in prostate cancer prevention. If this is true, I'm not sure how to selecively target ER-alpha apart from using I3C. All other estrogen blockers seem to target both so some degree.




    There are two estrogen receptors in this model:




    ER-alpha: accelerates prostate cancer




    ER-beta: puts the brakes on prostate cancer.




    It is believed that ER-alpha and ER-beta have a relationship to TMPRSS2-ERG gene fusions. These gene fusions are associated with more aggressive cancers and future diagnostics may use their presence as a marker to distinguish between indolent and aggressive prostate cancer. Also see [PMID: 18505969]



    Example: Toremifene. Toremifene is in a class of drug known as a selective estrogen receptor modulator (SERM). Low doses of toremifene act again ER-alpha and to a much lesser extent against ER-beta. Since ER-alpha accelerates the cancer the effect of toremifene is anti-cancer; however, at higher doses toremifene acts against not only ER-alpha but also against ER-beta so at these higher doses the ER-beta no longer counteracts the ER-alpha and so is no longer effective. This gives it an inverse dose response curve: i.e. toremifene is effective at lower dosages where it only knocks out ER-alpha but at higher dosages it is less effective or ineffective since it starts blocking the beneficial ER-beta as well.





    Example: phytoestrogens. Phytoestrogens have an anti-cancer effect via a pathway outside the scope of this model; however, they also bind to ER-beta which could have the effect of disabling ER-beta's moderating influence on prostate cancer and encouraging the formation of bcl-2, a protein which protects cancer cells. Particularly problematic might be if the patient simultaneously increased bcl-2 from multiple sources such as by consuming high amounts of phytoestrogens such as soy and at the same time generated even more bcl-2 by taking 5AR drugs or natural 5AR inhibitors such as saw palmetto and its key ingredient beta sitosterol or with white button mushrooms. See Ed Friedman's comments and more comments. "Green tea catechin (-)-epigallocatechin gallate (EGCG) is a natural AR5 inhibitor. Flavonoids that were potent inhibitors of the type 1 5alpha-reductase include myricetin, quercitin, baicalein, and fisetin. Biochanin A, daidzein, genistein, and kaempferol were much better inhibitors of the type 2 than the type 1 isozyme. Several other natural and synthetic polyphenolic compounds were more effective inhibitors of the type 1 than the type 2 isozyme, including alizarin, anthrarobin, gossypol, nordihydroguaiaretic acid, caffeic acid phenethyl ester, and octyl and dodecyl gallates." (quotes from [PMID: 11931850])


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    Doc.

    It's obviously up to you whether you respond or not but I have asked you to comment on this subject on several occasions and you continue to ignore this issue. I even post relevant studies. I'm just curious why?
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    My apologies if you feel that I have left your questions unanswered. I do my best to get to as many as are feasibly possible each day. Understand that contrary to perhaps popular belief...I am on the forums about 20 minutes per day; whatever is at the top of the subforum or in PMs, etc... is usually what I get to. Obviously, I accomplish more when responses warranted are small; but rarely is this the case. If I respond in a few words; more often than not I am talking to talk - and you can get that from many other posters.

    That said; as for your question - ER alpha and ER beta DO, in fact, have different expression; BUT you truly shouldn't look at them in isolation. Research has clearly demonstrated as a whole that estrogen receptor alpha-to-estrogen receptor beta expression ratio rather than the individual expression levels determines the fraction of DNA-binding homodimers of estrogen receptor alpha and possibly the growth potential in myometric (muscle) tissue.

    In the case of prostate pathology (in particular prostate cancer - which is found in highest incidence of all cancers on autopsy; so most will get it, regardless of whether or not you suffer true clinical deterioration, which has even lead most recently to screening methods and so on to be CHALLENGED; why look if it isn't truly causing as much death as we anticipate...however, those that choose to adopt treatment suffer many treatment side effects - it's actually a rather interesting debate), in human prostate cancer cells examined...BOTH ERB/ERA mRNAs were found. What has occured is NOT coincidental and ERB likely does NOT play a role in PROLIFERATION (expansion of cells)...thereby appearing "protective." What we also know, however, is that ERB in high expression does play a role in DIFFERENTIATION (changing of cells). It is superior to lower the ratio as a whole.

    When taken further...we also know yet still that 5α-androstane-3β,17β-diol (3β-androstanediol), a metabolite of dihydrotestosterone, has all the characteristics of the natural ligand for ERB. Finasteride, by blocking the conversion of testosterone to dihydrotestosterone, inhibits the production of 3β-androstanediol, thus suppressing ERB and preventing the differentiation of epithelium. This mechanism could account for the higher incidence of poorly differentiated tumors in the finasteride group in the Prostate Cancer Prevention Trial.

    So, unless you couple a 5ARI (like finasteride) with a ERB agonist; you will NOT likely see the same scenario. In that scenario, ratio trumps because you are talking about upregulation of DHT receptor in the presence of heightened estrogen (either ERA or ERA). By the way, in our muscle-building world; 5ARI are anti-androgenic; so dependent upon goal (and I anticipate it would be muscle gain in most cases on this forum)...you are likely going to avoid the 5ARI; in which case - lowering of both is superior and much more complete.

    I'm hoping I am explaining it in a way that makes at least some sense...this is actually a VERY complex issue! One that I might not be able to do justice with in the scope of a single thread as there are volumes written on this subject.


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    So, if the likelihood of prostate cancer is to be reduced (a complex issue I know) is it best to lower ER alpha along with DHT while attempting to maintain higher levels of ER beta? I3C targets ER alpha receptors and Saw Palmetto reduces DHT. Would this be a recommended protocol even thought lowering DHT may be counter productive as far as maximizing muscle is concerned? Or would it be better to use a sucide inhibitor, such as Formestane, and ignore DHT since is appears to be an estrogen antagonist.
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    Quote Originally Posted by BBB View Post
    So, if the likelihood of prostate cancer is to be reduced (a complex issue I know) is it best to lower ER alpha along with DHT while attempting to maintain higher levels of ER beta? I3C targets ER alpha receptors and Saw Palmetto reduces DHT.


    In terms of potential prostate pathology...yes.


    Would this be a recommended protocol even thought lowering DHT may be counter productive as far as maximizing muscle is concerned? Or would it be better to use a sucide inhibitor, such as Formestane, and ignore DHT since is appears to be an estrogen antagonist.
    To answer the first part question here is a qualified "it depends." What it depends on is the goals of the user.

    AIs in isolation, like formestane, have done an equally effective job at prevention in terms of prostate pathology while not even remotely attenuating muscle gain, and perhaps potentiating it with high likelihood of concomitant increases in androgens.

    If an AI is used, the need for a direct acting ER-alpha (I3C) agent is less-likely the case.


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