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1.
Prostate is one of the major targets for dihydrotestosterone (DHT), however this gland is also recognized as a nonclassical target for estrogen as it expresses both types of estrogen receptors (ER), especially ERbeta. Nevertheless, the concentrations of aromatase and estradiol in the prostate are low, indicating that estradiol may not be the only estrogenic molecule to play a role in the prostate. It is known that DHT can be metabolized to 5alpha-androstane-3beta,17beta-diol (3beta-diol), a hormone that binds to ERbeta but not to AR. The concentration of 3beta-diol in prostate is much higher than that of estradiol. Based on the high concentration of 3beta-diol and since this metabolite is a physiological ERbeta ligand, we hypothesized that 3beta-diol would be involved in the regulation of ERbeta expression. To test this hypothesis, adult male rats were submitted to castration followed by estradiol, DHT or 3beta-diol replacement. ERbeta and AR protein levels in the prostate were investigated by immunohistochemistry and Western blotting assays. The results showed that after castration, the structure of the prostate was dramatically changed and ERbeta and AR protein levels were decreased. Estradiol had just minor effects on the parameters analyzed. DHT-induced partial recovery of ERbeta while it was the most effective inductor of AR expression. Replacement with 3beta-diol-induced the highest levels of ERbeta, but was comparatively less effective in recovering the AR expression and the gland structure. These results offer evidence that one functional role of 3beta-diol in the prostate may be autoregulation of its natural receptor, ERbeta.  相似文献   

2.
Estrogen receptor-beta: recent lessons from in vivo studies   总被引:8,自引:0,他引:8  
The unexpected discovery of a second form of the estrogen receptor (ER), designated ERbeta, surprised and energized the field of estrogen research. In the 9 yr since its identification, the remarkable efforts from academic and industrial scientists of many disciplines have made significant progress in elucidating its biology. A powerful battery of tools, including knockout mice as well as a panel of receptor-selective agonists, has allowed an investigation into the role of ERbeta. To date, in vivo efficacy studies are limited to rodents. Current data indicate that ERbeta plays a minor role in mediating estrogen action in the uterus, on the hypothalamus/pituitary, the skeleton, and other classic estrogen target tissues. However, a clear role for ERbeta has been established in the ovary, cardiovascular system, and brain as well as in several animal models of inflammation including arthritis, endometriosis, inflammatory bowel disease, and sepsis. The next phase of research will focus on elucidating, at a molecular level, how ERbeta exerts these diverse effects and exploring the clinical utility of ERbeta-selective agonists.  相似文献   

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Breast cancer is one of the most common forms of cancer observed in women. Endogenous estrogen is thought to play a major role in its development and estrogen receptor blockers are the most important drugs in its treatment. It has long been thought that any conditions or exposures, which enhance estrogenic responses, would result in an increased risk for breast cancer. The discovery of the second estrogen receptor, ERbeta, which can have effects opposite to those of the well-known 'original' estrogen receptor (now called ERalpha) challenges this simplistic view. In order to understand breast cancer one must first understand how the normal breast is maintained. The functions of ERbeta in the breast remain to be defined but from what we have learnt about its activities in in vitro systems, this estrogen receptor may have a protective role in the breast. Studies in human and rodent breasts as well as in human breast cancer biopsies reveal that ERbeta is by far the more abundant of the two ERs. Despite the role of estrogen in proliferation of the breast, neither of the two ERs appears to located in epithelial cells which divide in response to estrogen. In order to define the functions of ERbeta in the normal and malignant breast, we have created mice in which the ERbeta gene has been inactivated. Studies of the breasts of ERbeta knock out mice (BERKO) revealed abnormal epithelial growth, overexpression of Ki67 and severe cystic breast disease as mice age.  相似文献   

5.
Several reports deal with possible effects of female sex hormones on human umbilical vein endothelial cells (HUVEC) including elasticity, activation of plasma membrane Na(+)/H(+) exchange, VEGF receptor Flk-1/KDR and many others. In contrast to those findings, some publications pointed out that HUVEC lack expression of both the estrogen receptor (ER) and/or the progesterone receptor (PR). Because the majority of these investigations were carried out at a time period, when only one ER and one PR was known, the aim of this study was the systematic analysis of ERalpha and ERbeta as well as PR-A and PR-B expression in HUVEC with specific monoclonal antibodies by immunocytochemistry and quantitative RT-PCR (TaqMan). As a result, we could show that HUVEC lack ERalpha but express ERbeta. The expression of ERbeta could be significantly upregulated with 17beta-estradiol on mRNA and protein level. In addition, HUVEC express PR-A but not PR-B. PR-A expression could be significantly upregulated with progesterone, again on mRNA and protein level. We conclude that estrogenic effects on HUVEC are mediated via the ERbeta and gestagens act via the PR-A pathway.  相似文献   

6.
Recently, Yang et al. reported that estrogen receptor beta (ERbeta) is a mitochondrial protein rather than a nuclear receptor. Because this claim would lead to a significant change in our understanding of estrogen signaling, we have attempted to reproduce the MALDI-TOF data of Yang et al. We separated proteins extracted from mouse liver mitochondria by SDS-PAGE and analysed a gel band covering the molecular weight range of 50-65 kDa by MALDI-TOF/TOF. Analysis of the data with the MASCOT database algorithm provided no evidence for the presence of ERbeta in the mitochondria. If we search (as the authors did) with only the peptide masses which match to tryptic fragments of ERbeta, ERbeta is identified with a significant score of 69. However, fragmentation of these peptides shows that they are not from ERbeta. Our conclusion is that ERbeta cannot be identified by MALDI-TOF from a mixture of mitochondrial proteins resolved on SDS-PAGE.  相似文献   

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Clinical management of breast cancer is increasingly guided by assessment of tumor phenotypic parameters. One of these is estrogen receptor (ER) status, currently defined by ERalpha expression. However with the discovery of a second ER, ERbeta and its variant isoforms, the definition of ER status is potentially more complex. In breast tumors there are two ERbeta expression cohorts. One where ERbeta is co-expressed with ERalpha and the other expressing ERbeta alone. In the latter subgroup of currently defined ER negative patients ERbeta has the potential to be a therapeutic target. Characterization of the nature and role of ERbeta in ERalpha negative tumors is essentially unexplored but available data suggest that the role of ERbeta may be different when co-expressed with ERalpha and when expressed alone. This review summarizes available data and explores the possibility that ERbeta signaling may be a therapeutic target in these tumors. Evidence so far supports the idea that the role of ERbeta in breast cancer is different in ERalpha negative compared to ERalpha positive tumors. However, cohort size and numbers of independent studies are small to date, and more studies are needed with better standardization of antibodies and protocols. Also, the ability to determine the role of ERbeta in ERalpha negative breast cancer and therefore assess ERbeta signaling pathways as therapeutic targets would be greatly facilitated by identification of specific downstream markers of ERbeta activity in breast cancer.  相似文献   

9.
Although a clear role for estrogen receptor (ER) alpha has been established, the contribution of ERbeta in estrogen-dependent development, growth and functions of the myometrium is not understood. As a first step towards understanding the role of ERbeta, we have examined the expression of ERalpha and ERbeta in the human myometrium. With competitive RT-PCR assays, the level of ERbeta mRNA was 10-200 times lower than that of ERalpha mRNA in both premenopausal and postmenopausal myometrium. In premenopausal myometrium, the expression pattern of ERbeta mRNA during the menstrual cycle was similar to that of ERalpha mRNA, with highest levels in peri-ovulatory phase. In postmenopausal myometrium, ERbeta mRNA was significantly higher than it was in premenopausal myometrium, while the level of ERalpha mRNA was lower. The net result was a change in the ratio of ERbeta to ERalpha mRNA expression. The ratio changed from 0.6-1.5 in premenopausal to 2.5-7.6 in postmenopausal myometrium. In premenopausal women, the gonadotropin releasing hormone analogue, leuprorelin acetate, elicited a decrease in ERalpha and an increase in ERbeta mRNA expression to cause a postmenopausal receptor phenotype. Estradiol, on the other hand, reversed ERalpha and ERbeta mRNA expression and their ratio in postmenopausal myometrium to those of premenopausal myometrium. Immunohistochemical staining and Western blot analysis of ERalpha and ERbeta with semiquantitative analysis showed good agreement between mRNA and protein levels. The data indicate that coordinated expression of ERalpha and ERbeta might be necessary for normal estrogen action in myometrium. Furthermore, estrogen appears a dominant regulator of both receptors in the myometrium.  相似文献   

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