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Query: UNIPROT:P06889 (Mol)
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Epidemiological and "in vitro" studies support a direct role of estrogens in the pathogenesis and/or progression of colorectal cancer (CRC). Recent observations suggest a local synthesis of 17beta-estradiol (E(2)). In the present study, the CRC estrogen receptor beta (ERbeta) positive HCT8, HCT116, DLD-1 and LoVo cell lines were evaluated for expression of functional 17beta-hydroxysteroid dehydrogenase (17betaHSD) types 1, 2, 3, and 4. RT-PCR analysis revealed that while 17betaHSD1 and 17betaHSD4 were expressed in all the four cell lines, 17betaHSD2 and 17betaHSD3 were expressed in a cell-specific manner. The interconversion of tritiated estrone (E(1)) or E(2) evaluated by thin layer chromatography of conditioned media revealed that in HCT8, HCT116, and DLD-1 cells both reductive and oxidative activities were present, the latter showing K(m) values (approximately 10 microM) 40-fold higher than the former (approximately 250 nM). On the contrary, in LoVo cells, estrogens were almost (approximately 90%) completely metabolized to hydrophile compounds. Charcoal-dextrane (DC) stripped fetal calf serum (FCS) (10%), E(2) (10nM), Vitamin D(3) (100nM) and the combined E(2) and Vitamin D(3) treatment were evaluated for modulation of 17betaHSD isoenzymes gene expression and activity. Gene expression and activity of 17betaHSD reductive and oxidative isoenzymes were respectively inhibited and enhanced by Vitamin D(3) in HCT8 and LoVo cells. Surprisingly, DC-FCS induced a marked increase of estrogen metabolism toward hydrophile metabolites in all four cell lines. In conclusion, our results clearly show that metabolism of estrogens by 17betaHSD isoenzymes is functional and modulated by external stimuli in continuous neoplastic colonic epithelial cell lines.
J Steroid Biochem Mol Biol 2002 Jul
PMID:Estrogen metabolism in human colorectal cancer cells. 1216 40

CYP1B1, a member of the cytochrome p450 superfamily, is expressed constitutively in the steroidogenic tissues of mammals and is inducible by peptide hormones, cAMP and aromatic hydrocarbon receptor (AHR) ligands. The mechanism of induction of this cytochrome p450 is similar to that for CYP1A1, i.e. through the aromatic hydrocarbon receptor (AHR) signaling pathway. We have recently reported that CYP1B1, but not CYP1A1, is expressed in rat granulosa cells (GC) in the absence of any external stimulus. The induction of CYP1B1 mRNA in rat GC by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in vitro was followed by an increase in AHR and estrogen receptor (ER-beta) RNA levels. Estrous cycle-dependent expression of AHR, AHR-nuclear translocator (ARNT) and ER-mRNAs in the rat ovary was reported. We suggest that CYP1B1 may play a major role in the regulation of rat ovarian function/cycle but until now this has been unexplored experimentally. The present study was therefore aimed at examining the expression of CYP1A1, CYP1B1 and ER-mRNA in rat ovarian tissues throughout the estrous cycle to establish any correlation in the expressions of these mRNAs in rat ovary. Total RNA was extracted from the ovary and liver of cycling adult rats and the mRNAs were analyzed using relative RT-PCR with gene-specific primers for the target mRNA and for RPL 19 or S16 primers as an internal control. The results indicated that in the ovary, CYP1B1 mRNA increased significantly on the evening of proestrus and dramatically decreased on the morning of estrus, while ER-mRNA remained unaltered throughout the estrous cycle. CYP1A1 mRNA in the ovary and both CYP1A1 and CYP1B1 mRNAs in the liver were undetectable. That the sudden decrease of ovarian CYP1B1 mRNA on the morning of estrus was not an effect of the LH surge was verified in vitro using our short-term GC culture model. GC prepared from rats super-stimulated with equine chorionic gonadotropin (eCG) were cultured for 6 h with or without LH and TCDD. It was observed that both CYP1A1 and CYP1B1 mRNAs were induced by TCDD with no apparent effect of LH. It is suggested that the high level of CYP1B1 mRNA expression on the evening of proestrus in rat ovary might be involved in metabolism of estrogens to catecholestrogen (a known effect of CYP1B1), and that expression is unaffected in GC by LH.
Comp Biochem Physiol B Biochem Mol Biol 2002 Sep
PMID:Estrous cycle-regulated expression of CYP1B1 mRNA in the rat ovary. 1222 20

Estrogen receptor beta (ERbeta) has been previously mapped in the rat central nervous system. This study aims to explore the regulation of ERbeta mRNA as it is expressed in the intact and cycling female rat brain. Young adult female rats (90+ day, N=20) were screened for estrous phases via vaginal cytology and sacrificed. Brains and blood were collected and processed for in situ hybridization and estradiol (E2) and progesterone (P4) hormone assays, respectively. ERbeta mRNA levels exhibited significant correlations with ovarian steroid ratios (E2/P4) in various brain regions, including the bed nucleus of stria terminalis, the medial nucleus of amygdala, and the anteroventral periventricular nuclei but not the paraventricular and the supraoptic nuclei or the preoptic area of the hypothalamus. No regulatory changes were detected in the cortex. Specifically, in the affected regions, higher P4 levels were significantly correlated with higher ERbeta mRNA expression. In contrast, there was a tendency for higher E2 levels to be correlated with lower ERbeta mRNA expression, but this tendency reached significance only in the bed nucleus of stria terminalis. These results suggest that ERbeta mRNA is regulated in the intact and cycling female rat hypothalamic as well as extrahypothalamic brain regions, and the circulating ovarian hormones play a critical role.
Brain Res Mol Brain Res 2002 Oct 15
PMID:Correlation of estrogen beta-receptor messenger RNA with endogenous levels of plasma estradiol and progesterone in the female rat hypothalamus, the bed nucleus of stria terminalis and the medial amygdala. 1239 62

Our recent report has revealed the existence of the progesterone receptor (PR) isoform S, which consists of the novel PR exon S and exons 4-8 of the PR gene in the human testicular cDNA library. More recently, we have cloned the human estrogen receptor alpha (ERalpha) isoform S cDNA from the library. The ERalpha isoform S cDNA also contains the novel ERalpha exon S and exons 4-8 of the ERalpha cDNA. Based on these findings, we assumed that the novel isoform of cDNA like the PR- and ERalpha isoforms might exist in the human ER beta (ERbeta). In order to investigate this possibility, we have screened the human testicular cDNA library using the exons 4-8 corresponding sequence of the human ERbeta cDNA. Consequently, we have cloned a novel isoform of the ERbeta cDNA that consists of a previously unidentified 5'-sequence and the exons 5-8 of the ERbeta gene. We termed this isoform cDNA the "ERbeta isoform M cDNA". The 5'-sequence of the ERbeta isoform M cDNA was confirmed to be derived from a novel exon (termed the "exon M") by analysis of the genomic DNA. Moreover, we have analyzed the molecular size of the ERbeta isoform M encoded by the ERbeta isoform M mRNA by transient expression of the ERbeta isoform M cDNA in the 293T cell. The approximately 28 kDa protein, which was recognized by the anti-rat ERbeta antibody against the carboxyl-terminal region, was synthesized in the cells. Thus, we concluded that the ATG in the exon M could be used as the translation initiation codon. This report revealed for the first time the existence of the ERbeta mRNA isoform that is not caused by the skipping of one or more exons, by the alternative usage of the multiple exon 8s, nor by the alternative utilization of the untranslated 5'-exons located on the upstream region of the exon 1.
J Steroid Biochem Mol Biol 2002 Oct
PMID:Cloning of the novel isoform of the estrogen receptor beta cDNA (ERbeta isoform M cDNA) from the human testicular cDNA library. 1247 86

Estrogens are suggested to be antiatherogenic by affecting the vessel wall components. Since ABCA1 was recently shown to be atheroprotective, it was examined if estrogen-induced atheroprotection occurs partly via the regulation of the ABCA1. Since hepatic ABCA1 expression was also suggested to contribute to the bulk HDL levels, regulation of the ABCA1 under conditions of high or low levels of HDL were investigated in mice expressing normal or elevated levels of apoAI. To delineate whether estrogen's effect occurs via estrogen receptor-alpha-mediated pathway, the estrogen receptor-alpha-deficient (ER-alpha)-/- mice were also administered either placebo or beta-estradiol for 5 consecutive days. Estrogen treatments decreased circulating HDL levels by 30%, but increased hepatic and intestinal ABCA1 mRNA by 2- and 1.5-fold, respectively. Hepatic ABCA1 mRNA also increased in the ER-alpha-/- mice by 3-fold. These results suggest that estrogen, despite lowering the levels of HDL, it up-regulated the hepatic ABCA1 mRNA, and in the absence of ER-alpha, ER-beta could compensate for ER-alpha. To study whether HDL levels correlate with the ABCA1 expression, wild-type (WT) and the apoAI transgenic (A1-Tg) mice were fed high fat (HF) diet with or without cholic acid (CA) for 3 weeks. One group of mice was treated with fenofibrate, known to elevate HDL levels. CA without HF decreased HDL levels, while fenofibrate increased HDL levels. However, neither CA nor fenofibrate altered hepatic ABCA1 mRNA levels. HF diet increased the hepatic ABCA1 mRNA 1.8-fold in WT, but lowered ABCA1 mRNA by 2-fold in A1-Tg mice, suggesting that ABCA1 levels did not correlate with circulating HDL levels, while basal levels of HDL influenced ABCA1 expression. These data show for the first time that estrogen's antiatherogenic effects may occur via ABCA1-mediated pathway, and circulating HDL levels may influence expression of ABCA1.
Mol Cell Biochem 2002 Nov
PMID:Estrogen-induced regulation of the ATP-binding cassette transporter A1 (ABCA1) in mice: a possible mechanism of atheroprotection by estrogen. 1248 73

Estrogen receptor (ER)-beta, unlike ER-alpha, is localized in the hypothalamic paraventricular nucleus (PVN) which also contains neuropeptide synthesizing neurons, such as oxytocin (OT), arginine vasopressin (AVP) and corticotropin-releasing hormone (CRH). Although it is known that some ER-beta containing neurons co-express OT and AVP, but not CRH, in the PVN, it is not yet determined whether ER-beta activation may indeed play a role in estrogenic regulation on syntheses of these neuropeptides. In the present study, we tested this hypothesis by comparing the effects of estrogen on the levels of OT, AVP and CRH messenger RNA (mRNA) between ER-beta knockout (betaERKO) and wild type (WT) control male mice. Mice were gonadectomized and implanted with either a pellet containing estradiol benzoate (2.5-5.0 microg/day) or a placebo pellet for 21 days. In situ hybridization histochemistry revealed that estrogen treatment resulted in a significant increase in OT transcripts (151.6+/-6.0%) and a decrease in AVP transcripts (77.8+/-5.2%) in the PVN of WT mice, compared to the placebo control group. This estrogenic regulation of OT and AVP mRNA levels in the PVN was completely abolished in betaERKO mice. Similar genotype differences in the effects of estrogen on the numbers of OT- and AVP-containing cells were found in immunocytochemical studies performed in a separate set of mice. On the other hand, the expression of CRH mRNA in the PVN was not affected by estrogen treatment in either WT or betaERKO mice. Furthermore, estrogen did not cause any changes in the levels of OT or AVP mRNA, regardless of genotype, in the supraoptic nucleus where, unlike in rats, ER-beta containing neurons are rarely found in mice. Finally, estrogen significantly increased OT mRNA levels in both betaERKO and WT in the medial preoptic area, which contains both ER-alpha and ER-beta. These results suggest that ER-beta activation may play a critical role in estrogenic regulation of OT and AVP gene expression in the PVN.
Brain Res Mol Brain Res 2002 Dec 30
PMID:Estrogen receptor-beta regulates transcript levels for oxytocin and arginine vasopressin in the hypothalamic paraventricular nucleus of male mice. 1253 18

Licorice root contains chemically diverse compounds that exhibit estrogenic effects in vitro and in vivo. The chalcone isoliquiritigenin (ISL) is a component of licorice extract exhibiting either antitumorigenic activity or estrogen receptor (ER) alpha-dependent growth promoting effects on breast cancer cells. In order to contribute to a better understanding of this apparent paradox, we synthesized and ascertained the estrogenic properties of ISL using, as model systems, the hormone-sensitive MCF7 breast cancer cells and the steroid-independent HeLa cells. Transfection experiments reveal that ISL is able to transactivate the endogenous ER alpha in MCF7 cells and this is supported by the capability to induce down-regulation of ER alpha protein levels and up-regulation of pS2 mRNA. Moreover, by using chimeric proteins consisting of the hormone binding domains of ER alpha and ER beta fused to the Gal4 DNA binding domain, we have determined that ISL is an estrogenic agonist of both ER isoforms. As a biological counterpart, low and intermediate ISL concentrations that induce substantial transcriptional activity stimulate the proliferation of MCF7 cells. However, high levels of ISL become cytotoxic even in steroid-receptor negative HeLa cells. Thus, the activity of ISL and the balance between risk or chemopreventive factor for estrogen-dependent breast cancer may depend on dietary intake.
J Steroid Biochem Mol Biol 2002 Nov
PMID:Estrogenic and antiproliferative activities of isoliquiritigenin in MCF7 breast cancer cells. 1258 38

Aromatase, the product of the CYP19 gene, plays a key role in androgenic steroids transformation into estrogens from various hormonal sensitive tissues. Thus, in situ expression of CYP19 has been suggested to be involved in breast tumor growth especially in post-menopausal patients.We developed a real-time quantitative RT-PCR assay based on fluorescent TaqMan methodology to quantify total CYP19 gene expression at the mRNA level in breast tumors. This method, based on nucleic acid quantification in homogeneous solutions, has the potential to become a standard in terms of its sensitivity, wide dynamic range and high-throughput capacity. In a well-defined series of 107 post-menopausal breast tumor samples, relative CYP19 mRNA levels ranged from 1 to 131. Among the four major CYP19 exon I-spliced transcripts, designated I.a, I.b, I.c and I.d, mRNA levels of the latter three correlated positively with total CYP19 mRNA levels. In ER alpha-positive breast tumors, CYP19 and ER alpha mRNA levels correlated negatively with each other (P=0.0078, r=-0.266), while CYP19 and ER beta mRNA levels correlated positively (P=0.00012, r=+0.388). Patients with high CYP19 mRNA levels did not relapse more frequently or have shorter relapse-free survival than other patients. Finally, mRNA levels of IL6, a major CYP19 regulatory factor, were significantly higher in tumors strongly expressing CYP19 than in tumors weakly expressing CYP19 (P=0.018). In conclusion, CYP19 expression did not influence the outcome of post-menopausal patients with breast cancer.
J Steroid Biochem Mol Biol 2002 Nov
PMID:Real-time reverse transcription PCR assay of CYP19 expression: application to a well-defined series of post-menopausal breast carcinomas. 1258 39

Levonorgestrel (LNG), a 19-nor-testosterone derivative, is widely used in contraceptive formulations. This compound does not bind to the estrogen receptor (ER), but it shows estrogen-like effects under in vivo and in vitro conditions. The estrogenicity of LNG may be attributed to its bio-transformation into non-phenolic metabolites. In this study, the ability of A-ring reduced LNG metabolites to activate transcription via an estrogenic mechanism of action, including differences between ER alpha and ER beta subtypes, were investigated. Transactivation assays were performed in HeLa cells transfected with expression vectors for ER alpha and ER beta and an estrogen-responsive reporter gene. Cells were also transfected with expression vectors for both progesterone receptor (PR) isoforms (A or B). As expected, the tetrahydro derivatives of LNG (3 alpha,5 alpha- and 3 beta,5 alpha-LNG) showed significantly lower PR-mediated transcriptional activities through both isoforms when compared with progesterone (P(4)) and LNG. In contrast, the 3 beta,5 alpha-tetrahydro derivative resulted in a significant activation of estrogen-dependent gene transcription. This effect was selectively confined to the ER alpha, since little if any activity could be observed with the ER beta and no antagonistic activities were demonstrated. This study provides structural and molecular clues for the well documented in vitro and in vivo intrinsic estrogenicity of 19-nor-testosterone-derived progestins and ligand requirements for ER alpha recognition.
J Steroid Biochem Mol Biol 2002 Nov
PMID:The intrinsic transcriptional estrogenic activity of a non-phenolic derivative of levonorgestrel is mediated via the estrogen receptor-alpha. 1258 40

The ability to rescue viable prostate precursor tissue from Rb-/-fetal mice has allowed for the generation of Rb-/-prostate tissue and Rb-/-prostate epithelial cell lines. Herein, we provide a protocol for the rescue of urogenital precursor tissue from mouse embryos harboring the lethal Rb-/-mutation. The rescued precursors can matured as subrenal capsule grafts in athymic mice. Subsequently prostatic tissue can be used as a source for Rb-/-epithelium in a tissue recombination protocol for the generation of chimeric prostate grafts in athymic male mouse hosts. We have also provided a detailed description for isolating and propagating the Rb-/-epithelium from such tissue recombinants as established cell lines. Methods for characterizing the grafts and cell lines by determining the retention of prostate-specific epithelial expression markers, including cytokeratins, the androgen receptor, estrogen receptor beta and the dorsolateral prostatic secretory protein (mDLP) are given.
Methods Mol Biol 2003
PMID:Rescue and isolation of Rb-deficient prostate epithelium by tissue recombination. 1261 9


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