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.
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])