• BMB Reports
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• v.44 no.7
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• pp.452-457
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• 2011

The Egr-1 is an immediate early response gene encoding a transcription factor that functions in the regulation of cell growth, differentiation, and apoptosis. Estrogen has diverse physiological effects, including cellular proliferation and neuroprotection against brain injury. There are two types of estrogen receptors (ERs), $ER{\alpha}$ and $ER{\beta}$. $ER{\alpha}$-induced Egr-1 expression has been extensively studied; however, the role of $ER{\beta}$ is yet not known. In the present study, we investigated whether or not $ER{\beta}$ induces Egr-1 expression in C6 rat glioma cells, which express $ER{\beta}$ but not $ER{\alpha}$. Our results show that $ER{\beta}$ promoted up-regulation of Egr-1 expression via a non-genomic mechanism involving the Raf/MEK1/Erk/Elk-1 signaling cascade.

• Bulletin of the Korean Chemical Society
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• v.29 no.6
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• pp.1107-1114
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• 2008

It is important to identify selective ligands for the estrogen receptor subtypes ER$\alpha$ or ER$\beta$ to evaluate them as pharmaceutical targets in breast cancer. To develop ER$\beta$-selective ligands as PET imaging agents, a series of aryl indazole estrogen analogues substituted at the C3 position with fluoroethyl and fluoropropyl groups were synthesized and evaluated for their relative binding affinities and selectivities for ER$\alpha$ vs ER$\beta$. The fluoroethylated indazole estrogen (FEIE, 1i) and fluoropropylated indazole estrogen (FPIE, 1h) showed 41- fold and 17-fold ER$\beta$/ER$\alpha$ selectivity, respectively. However, their binding affinities to ER$\alpha$ and ER$\beta$ were very low.

• Molecules and Cells
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• v.26 no.5
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• pp.454-458
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• 2008

Sex steroid hormone receptors play a central role in modulating telomerase activity, especially in cancer cells. However, information on the regulation of steroid hormone receptors and their distinct functions on telomerase activity within the mesenchymal stem cell are largely unavailable due to low telomerase activity in the cell. In this study, the effects of estrogen ($E_2$) treatment and function of estrogen receptor alpha ($ER{\alpha}$) and estrogen receptor beta ($ER{\beta}$) on telomerase activity were investigated in human mesenchymal stem cells (hMSCs). Telomerase activity and mRNA expression of the catalytic subunit of telomerase (hTERT) were upregulated by treatment of the cells with $E_2$. The protein concentration of $ER{\alpha}$ was also increased by $E_2$ treatment, and enhancement of $ER{\alpha}$ accumulation in the nucleus was clearly detected with immunocytochemistry. When $ER{\alpha}$ expression was reduced by siRNA transfection into hMSCs, the effect of $E_2$ on the induction of hTERT expression and telomerase activity was diminished. In contrast, the transient overexpression of $ER{\alpha}$ increased the effect of $E_2$ on the expression of hTERT mRNA. These findings indicate that the activation of hTERT expression and telomerase activity by $E_2$ in hMSCs depends on $ER{\alpha}$, but not on $ER{\beta}$.

• YAKHAK HOEJI
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• v.54 no.2
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• pp.102-105
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• 2010

Our previous results showed that hypoxia inducible factor-1 (HIF-1) activated estrogen receptor (ER) in the absence of ligand. In this study, we have studied the effect ER overexpression on the activation of HIF-1. ER overexpression induced transcription activation of hypoxia response element driven luciferase and vascular endothelial growth factor. As a negative control, the effect of ER on androgen receptor response element was used. Our result indicate that the two ER$\alpha$ and HIF-1 signaling pathways shares part of the activation pathway.

• Development and Reproduction
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• v.4 no.2
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• pp.215-220
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• 2000

Most of endocrine disrupters (EDs) have been reported to exhibit estrogenic or anti-androgenic activity and thereby may disrupt reproductive development in human or wildlife. This study was performed to investigate the effects of estrogen (E$_2$), bisphenol (BP) and octylphenol (OP) on the mouse Leydig cell line (TM3). TM3 originated from testis of 11~13-daly-old BALB/c nu/＋ mice was cultured in DMEM supplemented with 10％ FBS alone or medium with estrogen (E$_2$), bisphenol (BP) and octylphenol (OP; 1 pM, 1 nM, 1 $\mu$M, 1 mM, respectively) for 48 hours. After culture, total cell number and viability were assessed by heamocyto-meter and trypan blue stain. Expression of cytochrome P450scc (CYPscc) mRNA whose product is involved in steroid hormone biosynthesis and estrogen receptor $\alpha$(ER $\alpha$) mRNA were detected by RT-PCR. As a result, treatment of TM3 with E$_2$, BP and OP(1 mM, respectively) significantly decreased the viability but not all of groups as high as 1 $\mu$M. Exposure of TM3 to OP significantly reduced the total cell number but not E$_2$ or BP. The expression of CYPscc mRNA was slightly reduced in BP (1 nM, 1 $\mu$M) and significantly decreased in OP (1 nM, 1 $\mu$M) treated TM3, except E$_2$ group. But the expression of ER $\alpha$ mRNA was sightly increased in all treated groups. In conclusion, BP and OP (high concentration) might inhibit steroidogenesis by decreasing the CYPscc mRNA expression in the mouse testis. These results suggest that BP and OP might impair spermatogenesis and subsequently disturb testicular function.

• Development and Reproduction
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• v.23 no.4
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• pp.333-344
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• 2019

In vertebrate reproductive system, estrogen receptor (ER) plays a pivotal role in mediation of estrogenic signaling pathways. In the present study, we report the cDNA cloning, expression analysis, and transcriptional activity of ERβ1 subtype from medaka Oryzias dancena. The deduced O. dancena ERβ1 (odERβ1; 519 amino acids) contained six characteristic A/B to E/F domains with very short activation function 2 region (called AF2). A phylogenetic analysis indicated that odERβ1 was highly conserved among teleost ERβ1 subgroup. A conventional RT-PCR revealed that the odERβ1 transcripts were widely distributed in the multiple tissues, the ovary, brain, gill, intestine, kidney, and muscle. Further, the relatively higher odERβ1 expressions in the ovary and brain were clearly reproduced in RT-qPCR assay. When HA-fused odERβ1 expression vector was transfected into HEK293 cells, an immunoreactivity for odERβ1 was mainly detected in the nucleus part. Finally, an estrogen responsive element driven luciferase reporter assays demonstrated that the transcriptional activity of odERβ1 significantly increased by estradiol-17β (E2) in a dose dependent manner (p<0.05). However, fold-activation of odERβ1 in the presence of E2 was markedly weak, when it compared with those of O. latipes ERβ1. Taken together, these data suggest that odERβ1 represents a functional variant of teleost ERβ subtype and provides a basic tool allowing future studies examining the function of F domain of ERβ1 subtype and expanding our knowledge of ERβ evolution.

• Natural Product Sciences
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• v.25 no.1
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• pp.28-33
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• 2019

A popular approach for the study of estrogen receptor ${\alpha}$ inhibition is to investigate the protein-protein interaction between the estrogen receptor (ER) and the coactivator surface. In our study, we investigated phytochemicals from Rubus coreanus that were able to disrupt $ER{\alpha}$ and coactivator interaction with an $ER{\alpha}$ antagonist. The E-screen assay and molecular docking analysis were performed to evaluate the effects of the estrogenic activity of R. coreanus extract and its constituents on the MCF-7 human breast cancer cell line. At $100{\mu}g/mL$, R. coreanus extract significantly stimulated cell proliferation ($574.57{\pm}8.56%$). Sanguiin H6, which was isolated from R. coreanus, demonstrated the strongest affinity for the $ER{\alpha}$ coactivator-binding site in molecular docking analysis, with a binding energy of -250.149. The initial results of the study indicated that sanguiin H6 contributed to the estrogenic activity of R. coreanus through the activation of the $ER{\alpha}$ coactivator-binding site.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.6
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• pp.2935-2940
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• 2016

Breast cancer is the most frequent type of cancer diagnosed among women worldwide and also in Thailand. Estrogen and estrogen receptors exert important roles in its genesis and progression. Several cytokines have been reported to be involved in the microenvironment that promotes distant metastasis via modulation of immune and inflammatory responses to tumor cells. Estrogen receptor genetic polymorphisms and several cytokines have been reported to be associated with breast cancer susceptibility and aggressiveness. To investigate roles of genetic polymorphisms in estrogen receptor alpha (ESR1) and interleukin 6 (IL6), breast cancer patients and control subjects were recruited from the Division of Head, Neck and Breast Surgery (Siriraj Hospital, Bangkok, Thailand). Polymorphisms in ESR1 (rs3798577) and IL6 (rs1800795 and rs1800797) were evaluated by real-time PCR in 391 breast cancer patients and 79 healthy controls. Associations between genetic polymorphisms and clinicopathological data were determined. There was no association between genetic polymorphisms and breast cancer susceptibility. However the ESR1 rs3798577 CT genotype was associated with presence of lymphovascular invasion (OR=2.07, 95%CI 1.20-3.56, p=0.009) when compared to the TT genotype. IL6 rs1800795 CC genotype was associated with presence of extranodal extension (OR= 2.30, 95%CI 1.23-4.31, p=0.009) when compared to the GG genotype. Survival analysis showed that IL6 rs1800797 AG or AA genotypes were associated with lower disease-free survival. These findings indicate that polymorphisms in ESR1 and IL6 contribute to aggressiveness of breast cancer and may be used to identify high risk patients.

• Journal of the Korean Society of Food Science and Nutrition
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• v.33 no.9
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• pp.1486-1491
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• 2004

The estrogenicities of six heavy metal compounds, which contaminate frequently in foods, were assayed using a combination of in vitro and in vivo assays. The assays were 1) estrogen receptor dependent transcriptional expression assay, 2) E-screen assay and, 3) the uterotropic assay in mice. The chemicals studied were 17$\beta$ -estradiol, diethylstilbestrol (DES), arsenic oxide, bis(tri-n-butyltin), cadmium chloride, chromium chloride, lead acetate, and mercuric chloride. Using the estrogen receptor dependent transcriptional expression assay, the following estrogenicity ranking was measured: bis(tri-n-butyltin) > cadmium chloride > chromium chloride >> mercuric chloride >lead acetate = arsenic oxide. Using E-screen test, the following estrogenicity ranking was measured: bis(tri-n-butyltin) > cadmium chloride > chromium chloride >> mercuric chloride > lead acetate = arsenic oxide. Results from the uterotropic assay showed that bis(tri-n-butyltin), cadmium chloride, chromium chloride caused an increase in uterine wet weight, while lead acetate, mercuric chloride, and arsenic oxide failed to do so. Bis(tri-n-butyltin), cadmium chloride and chromium chloride showed the highest estrogenicity in three assay systems. Recent studies suggesting that bis(tri-n-butyltin), cadmium chloride have estrogenicities are compatible with the present finding. Furthermore, our study is suggesting that chromium chloride may be estrogenic. The results demonstrate that this three level-assay combination (transcriptional activation, cell proliferation, and an in vivo effect in an estrogen-responsive tissue) could serve as a useful method to assess the estrogenicity of heavy metals.

• Biomolecules & Therapeutics
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• v.22 no.4
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• pp.347-354
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• 2014

Larrea nitida is a plant that belongs to the Zygophyllaceae family and is widely used in South America to treat inflammatory diseases, tumors and menstrual pain. However, its pharmacological activity remains unclear. In this study we evaluated the property of selective estrogen receptor modulator (SERM) of Larrea nitida extracts (LNE) as a phytoestrogen that can mimic, modulate or disrupt the actions of endogenous estrogens, depending on the tissue and relative amount of other SERMs. To investigate the property of SERM of LNE, we performed MCF-7 cell proliferation assays, estrogen response element (ERE)-luciferase reporter gene assay, human estrogen receptor (hER) binding assays and in vivo uterotrophic assay. To gain insight into the active principles, we performed a bioassay-guided analysis of LNE employing solvents of various polarities and using classical column chromatography, which yielded 16 fractions (LNs). LNE showed high binding affinities for $hER{\alpha}$ and $hER{\beta}$ with $IC_{50}$ values of $1.20{\times}10^{-7}$ g/ml and $1.00{\times}10^{-7}$ g/ml, respectively. LNE induced $17{\beta}$-estradiol (E2)-induced MCF-7 cell proliferation, however, it reduced the proliferation in the presence of E2. Furthermore, LNE had an atrophic effect in the uterus of immature rats through reducing the expression level of progesterone receptor (PR) proteins. LN08 and LN10 had more potent affinities for binding on $hER{\alpha}$ and ${\beta}$ than other fractions. Our results indicate that LNE had higher binding affinities for $hER{\beta}$ than $hER{\alpha}$, and showed SERM properties in MCF-7 breast cancer cells and the rat uterus. LNE may be useful for the treatment of estrogen-related conditions, such as female cancers and menopause.