Characterization and measurement of cytoplasmic and nuclear oestradiol-17β-receptor proteins in benign hypertrophied human prostate

Auf, G.; Ghanadian, R.

doi:10.1677/joe.0.0930305

Cited by 21 publications

(4 citation statements)

References 20 publications

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“…However, androst-5-ene-3fl, 17fl-diol glucuronide is dramatically diminished from 1.29 k 0.11 (control group) to 0.65 f 0.13 ng/ml in patients with BPH (p < 0.01), also favoring an augmentation of plasma unconjugated androst-5-ene-3fl,17fl-diol. As was shown previously [8], there is no marked difference of plasma testosterone levekbetween the normal and the BPH group (Fig. 2), and the present study further shows that its glucuronide derivative is also unaffected.…”

Section: Resultssupporting

confidence: 91%

“…In the present study, we have observed an increase of plasma androst-5-ene-3P,17P-diol levels, indicating that, in men with BPH, the amount of plasma estrogenic steroid is increased in plasma. Since prostatic tissue contains estrogenic receptors [8], this change in circulating androst-5-ene-3P, 17P-diol could play a role in the process of hypertrophy. It is remarkable that, in the present study, we observed a decrease of glucuronidation of three steroids related to estrogenic action, ie, androst-5-ene-3P, 17P-dio1, estrone, and estradiol.…”

Section: Discussionmentioning

confidence: 99%

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Comparative Study of Plasma Steroid and Steroid Glucuronide Levels in Normal Men and in Men With Benign Prostatic Hyperplasia

Brochu

Bélanger

1988

Journal of Urology

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Plasma steroids were analyzed in 16 normal men and in 10 men with prostatic benign hyperplasia (BPH). The steroids measured by radioimmunoassay include pregnenolone, 17-OH-pregnenolone, dehydroepiandrosterone, androst-5-ene-36, 170-dio1, testosterone, dihydrotestosterone, androstane-3q 17P-dio1, androstane-36, 17P-dio1, estrone, and estradiol as well as their glucuronide derivatives. In addition, cortisol and the sulphoconjugated form of dehydroepiandrosterone were determined. Whereas the levels of pregnenolone, pregnenolone glucuronide and 17-OH-pregnenolone glucuronide are not different in the two groups, the levels of 17-OH-pregnenolone in the BPH group (0.87 f 0.07 ng/ml) exceed by twofold (p < 0.01) those observed in normal men. Plasma dehydroepiandrosterone and androst-5-ene-36, 176-diol concentrations are markedly elevated in the BPH group (1.49 + 0.23 and 0.55 f 0.08 ngiml vs the control groups 0.43 & 0.11 and 0.31 + 0.05 ng/ml, respectively). Since the plasma cortisol and pregnenolone levels are comparable in these two groups, our data suggest that the elevation of plasma 17-OH-pregnenolone, dehydroepiandrosterone, and androst-5-ene-36, 176-diol reflects an increase of adrenal 17-hydroxylase activity in patients with BPH. A slight increase of the plasma dihydrotestosterone and androsterone glucuronide concentration is also observed in men with BPH, indicating an increase of 5a-reduced androgen formation. We have also observed, in the BPH group, a 50% decrease (p < 0.01) of plasma glucuronidated androst-5-ene-30,170-diol, estrone, and estradiol levels, suggesting that the transformation of unconjugated estrogenic steroids into glucuronide derivative is inhibited in BPH patients. In summary, our data indicate that adrenal C-19 steroids might be involved in the process of BPH. Furthermore, whereas the estrogen glucuronide formation is diminished in men with BPH, the prostatic androgen metabolism as reflected by plasma dihydrotestosterone and androsterone glucuronide concentrations seems to be increased.

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Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Comparative Study of Plasma Steroid and Steroid Glucuronide Levels in Normal Men and in Men With Benign Prostatic Hyperplasia

Brochu

Bélanger

1988

Journal of Urology

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“…Androgen-estrogen synergism has been shown to facilitate development of prostatic epithelial hyperplasia in the dog [37], but there is no evidence that synergism is operative in human BPH, where stromal hyperplasia predominates. An estrogen receptor-like protein has been reported in some samples of NHP cytosol [ 14,381 and nuclei [39,40]. We observed in this study that a major proportion of the ER sites in human prostate are incompletely labeled during short-term incubation as utilized by others.…”

Section: Discussionsupporting

confidence: 50%

Sex Steroid Receptors in Normal and Hyperplastic Human Prostate

et al. 1985

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The concentrations of sex steroid receptors (per unit DNA) were measured in normal periurethral and peripheral prostatic tissue samples from seven men (mean age 64 years; range 54-71 years) undergoing cystectomy for bladder cancer, and in hyperplastic nodules from 15 men with BPH (mean age 69 years; range 60-89). Occupied androgen (AR) and estrogen (ER) receptors were measured with an improved exchange procedure, where receptor-binding sites were stabilized by a combinatorial procedure involving (1) careful washout of extracellular secretory products (including proteases) prior to homogenization, (2) inclusion of 0.5 mM phenylmethyl sulfonylfluoride (PMSF) and 20 mh4 molybdate in the exchange medium, and (3) long-term incubation at 04°C. Bound radioligands were separated by a hydroxylapatite (HAP) batch adsorption procedure. Maximal specific exchange binding of 3H-R 1881 or 3Hestradiol in total homogenates of human prostate samples was achieved after incubation periods of about 72 h at W'C. In contrast, progestin receptors (PR) were readily available for binding 3H-R 5020; thus overnight binding at 0-4°C was routinely used to measure PR. Binding specificities and equilibrium binding constants (calculated from 8-point Scatchard plots, correcting for nonsaturable binding) were found to be characteristic for AR, PR, and ER, respectively. The receptor results obtained in this study demonstrate that (1) no significant differences existed in total AR per unit DNA between hyperplastic and either central or peripheral prostatic tissue samples; (2) PR was present in both zones of normal prostatic tissue as often as in BPH samples, with PR concentrations significantly lower in hyperplastic samples; and (3) ER was irregularly detected in both normal and hyperplastic tissue in low concentration relative to AR and PR; the frequency of ER detection was much lower in BPH than in normal prostate tissue. Studies of steroid receptor content relative to enzyme markers specific for epithelial and stromal cells in BPH samples showed a positive correlation between acid phosphatase activity (a specific marker for epithelial cells) and both AR and PR. No correIation was observed between AR or PR with either prolyl hydroxylase. or myosin ATPase (specific markers for stromal cells). These observations suggest that PR, as well as AR, is primarily associated with the epithelial elements of prostate. Because of the relative infrequency of ER, similar correlation of ER with enzyme markers was not possible.

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“…The actions mediated by the estrogen receptors α and β in the prostate seem to be of opposite character (56)(57)(58). In the rodent prostate, ERβ has been reported to be present in the epithelial cells throughout the normal organ.…”

Section: Estrogens and Prostate Cancermentioning

confidence: 99%

Targeting estrogen- and hedgehog-signaling pathways in prostate cancer

Slusarz

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Prostate cancer is the second most frequent cause of cancer deaths in men, and the risk to develop cancer increases with age. Since the lifespan of the society is progressively increasing, the importance of preventing the development of this common disease is becoming more urgent. The prevention and therapy options for non-metastatic prostate cancer are available but limited. For the androgen-insensitive, metastatic form of prostate cancer there still is no effective therapy. Our laboratory has an estrogen receptor based perspective on prostate cancer. We are using a transgenic mouse as an animal model to study the development and treatment of prostate cancer. We are also investigating a selection of botanical compounds that have been implicated as cancer protective either by traditional medicine or in modern cancer research. The TRAMP (TRansgenic Adenocarcinoma of the Mouse Prostate) model enables us to study the specific roles of estrogen receptors in prostate cancer progression. The expression of the two estrogen receptors alpha (ER[alpha]) and beta (ER[beta]) in TRAMP mouse prostates switches upon progression from non-metastatic to metastatic tumor phenotype. During earlier stages of cancer, ER[beta] is the main estrogen receptor present, as the phenotype of the cancer changes to the more neuro-endocrine like, the expression of ER[beta] decreases and ER[alpha] seems to remain the only active receptor. Initial studies in the Lubahn lab and elsewhere led us to hypothesize a protective role for ER[beta] in prostate cancer tumorigenesis. The presence of ER[beta] only seems to prevent or slow down the incidence of (PDC) poorly differentiated carcinoma in contrast to ER[alpha], which promotes the metastatic, neuro-endocrine like phenotype. We have found though a study in double transgenic mice, that were WT and KO for estrogen receptors alpha or beta on a TRAMP background, that ER[alpha]KO mice did not develop poorly differentiated carcinoma (75 percent reduction compared to control animals), however ER[beta]KO mice had significantly increased PDC incidence and had double the PDC compared to animals WT for both receptors. We were also interested in cancer protective properties of a variety of botanical compounds, reported in the literature to be potentially beneficial for prostate health, and widely bought through health food stores around the country. We specifically investigated apigenin, baicalein, curcumin, EGCG, genistein, quercetin, and resveratrol, both in vitro and in vivo. All seven compounds were able to delay prostate cancer cell growth of both human (LNCaP, PC3, and PC3M) and mouse (TRAMP-C2) prostate cancer cell lines. All seven compounds combinations were also able to inhibit or delay prostate cancer incidence by up to 80 percent, specifically at the well differentiated carcinoma stage, when fed to TRAMP mice. The protective effects were only present in ERWT mice, indicating a need for both receptors for these compounds to act on the prostate cancer incidence. I introduced a new pathway to the lab, the hedgehog signaling pathway, which has been recently found to play a role in prostate cancer, specifically in metastatic cancer. Several botanicals used in the lab were able to inhibit the hedgehog pathway as indicated by decreasing Gli1 levels. With IC[subscript 50] values ranging from <1µM to 25µM these compounds demonstrated hedgehog pathway inhibition by deceasing Gli1 mRNA concentration by up to 95 percent and down regulating Gli-reporter activity by 80 percent. Also, both estrogen and ICI inhibit Gli1 mRNA in TRAMP-C2 cells, and Gli-reporter activity in Shh Light II cells. My research sheds light on an additional mechanism by which phytoestrogens are potentially protecting against cancer. My work suggests a potential new treatment target for addressing both slow and fast growing prostate cancers. Based on data presented here, we propose that a combination of ER[alpha] antagonists, ER[beta] agonists and selected botanicals should present a comprehensive prostate cancer remedy.

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Characterization and measurement of cytoplasmic and nuclear oestradiol-17β-receptor proteins in benign hypertrophied human prostate

Cited by 21 publications

References 20 publications

Comparative Study of Plasma Steroid and Steroid Glucuronide Levels in Normal Men and in Men With Benign Prostatic Hyperplasia

Comparative Study of Plasma Steroid and Steroid Glucuronide Levels in Normal Men and in Men With Benign Prostatic Hyperplasia

Sex Steroid Receptors in Normal and Hyperplastic Human Prostate

Targeting estrogen- and hedgehog-signaling pathways in prostate cancer

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