• Journal of Korean Biological Nursing Science
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• v.10 no.1
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• pp.80-87
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• 2008

Purpose: Hypoestrogenism caused by ovariectomy, disease, or menopause is associated with increased obesity in women. Altered fat distribution and weight gain are consequences of menopausal hypoestrogenism, but the mechanisms responsible are not completely known. This study examined the effect of estrogen on obesity in ovariectomized rats. Method: The groups of female rats were 4 weeks post ovariectomy (OVX) or, 4 weeks post-sham operation (SHAM), and 2 weeks post ovariectomy followed by 2 weeks replacement with estradiol benzoate (ER-$16{\mu}g$/kg, subq, qd). Serum ghrelin level was measured by radioimmunoassay (RIA). The expression of adrenergic receptors in adipose tissue was measured by Western blotting assay. Result: OVX significantly increased body weight, serum cholesterol. Two weeks estrogen replacement reduced body weight accompanied by the increment of serum ghrelin and the reduction of the receptor ratio of adrenergic ${\alpha}_{2A}/{\beta}_1$, and ${\alpha}_{2A}/{\beta}_3$. Conclusion: We provide evidence that estrogen reduces obesity through the altered receptor ratio of adrenergic ${\alpha}_{2A}/{\beta}_1$, and ${\alpha}_{2A}/{\beta}_3$ in adipose tissue in ovariectomized rats.

• Journal of Microbiology and Biotechnology
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• v.22 no.3
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• pp.378-384
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• 2012

In aquatic invertebrates, particularly marine gastropods, organotin compounds induce irreversible sexual abnormality in females, which is termed imposex, at very low concentrations. Organotin compounds are agonists for nuclear receptors such as RXRs and $PPAR{\gamma}$. However, the imposex phenomenon has not been reported to act as an antagonist on estrogen receptors in other species, including vertebrates and invertebrates. In order to gain insights into the antagonistic activity of organotin compounds on estrogen receptors (ERs), we examined the inhibitive effect of these compounds on estradiol-dependent ${\beta}$-galactosidase activity using the yeast two-hybrid detection system consisting of a combination of the human estrogen receptor ($hER{\beta}$) ligand-binding domain and the co-activator steroid receptor co-activator-1 (SRC1). Tributyltin-hydroxide (TBT-OH) and triphenyltin-chlorine (TPT-Cl) exhibited an inhibitive effect on $E_2$-dependent transcriptional activity, similar to antagonistic chemicals such as 4-hydroxytamoxifen (OHT) or ICI 182,780, at a very low concentration of $10^{-14}$ M TBT or $10^{-10}$ M TPT, respectively. The yeast growth and transcriptional activity with transcriptional factor GAL4 did not exhibit any effect at the tested concentration of TBT or TPT. Moreover, the yeast two-hybrid system using the interaction between p53 and the T antigen of SV40 large did not describe any effect at the tested concentration of OHT or ICI 182,780. However, the interaction between p53 and T antigen was inhibited at a TBT or TPT concentration of $10^{-9}$ M, respectively. These results indicate that TBT and TPT act as inhibitors of ER-dependent reporter gene transcriptional activation and of the interaction between $hER{\beta}$ LBD and the co-activator SRC1 in the yeast two-hybrid system. Consequently, our data could partly explain the occurrence of organotin compound-induced imposex on the endocrine system of mammals, including humans.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.11
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• pp.6761-6767
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• 2013

The nuclear receptor, peroxisome proliferator-activated receptor gamma ($PPAR{\gamma}$), is expressed in various cancer cells including breast, prostate, colorectal and cervical examples. An endogenous ligand of $PPAR{\gamma}$, 15-deoxy-${\Delta}^{12,14}$ prostaglandin $J_2$ (PGJ2), is emerging as a potent anticancer agent but the exact mechanism has not been fully elucidated, especially in breast cancer. The present study compared the anticancer effects of PGJ2 on estrogen receptor alpha ($ER{\alpha}$)-positive (MCF-7) and $ER{\alpha}$-negative (MDA-MB-231) human breast cancer cells. Based on the reported signalling cross-talk between $ER{\alpha}$ and $ER{\alpha}$, the effect of the $ER{\alpha}$ ligand, $17{\beta}$-estradiol (E2) on the anticancer activities of PGJ2 in both types of cells was also explored. Here we report that PGJ2 inhibited proliferation of both MCF-7 and MDA-MB-231 cells by inducing apoptotic cell death with active involvement of mitochondria. The presence of E2 potentiated PGJ2-induced apoptosis in MCF-7, but not in MDA-MB-231 cells. The $ER{\alpha}$ antagonist, GW9662, failed to block PGJ2-induced activities but potentiated its effects in MCF-7 cells, instead. Interestingly, GW9662 also proved capable of inducing apoptotic cell death. It can be concluded that E2 enhances $ER{\alpha}$-independent anticancer effects of PGJ2 in the presence of its receptor.

• BMB Reports
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• v.52 no.11
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• pp.647-652
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• 2019

G protein-coupled estrogen receptor (GPER) is known to play an important role in hormone-associated cancers. G-1, a novel synthetic GPER agonist, has been reported to exhibit anti-carcinogenic properties. However, the chemotherapeutic mechanism of GPER is yet unclear. Here, we evaluated GPER expression in human gastric cancer tissues and cells. We found that G-1 treatment attenuates GPER expression in gastric cancer. GPER expression increased G-1-induced antitumor effects in mouse xenograft model. We analyzed the effects of knockdown/overexpression of GPER on G-1-induced cell death in cancer cells. Increased GPER expression in human gastric cancer cells increased G-1-induced cell death via increased levels of cleaved caspase-3, -9, and cleaved poly ADP-ribose polymerase. Interestingly, during G-1-induced cell death, GPER mRNA and protein expression was attenuated and associated with ER stress-induced expression of PERK, ATF-4, GRP-78, and CHOP. Furthermore, PERK-dependent induction of ER stress activation increased G-1-induced cell death, whereas PERK silencing decreased cell death and increased drug sensitivity. Taken together, the data suggest that the induction of ER stress via GPER expression may increase G-1-induced cell death in gastric cancer cells. These results may contribute to a new paradigm shift in gastric cancer therapy.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.15
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• pp.6247-6251
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• 2014

Background: The aim of the present study was to investigate the involvement of emodin on the growth of human breast cancer MCF-7 and MDA-MB-231 cells and the estrogen (E2) signal pathway in vitro. Materials and Methods: MTT assays were used to detect the effects of emodin on E2 induced proliferation of MCF-7 and MDA-MB-231 cells. Flow cytometry (FCM) was applied to determine the effect of emodin on E2-induced apoptosis of MCF-7 cells. Western blotting allowed detection of the effects of emodin on the expression of estrogen receptor ${\alpha}$, cyclin D1 and B-cell lymphoma-2 (Bcl-2), mitogen-activated protein kinases (MAPK) and phosphatidylinostiol 3-kinases (PI3K). Luciferase assays were emplyed to assess transcriptional activity of $ER{\alpha}$. Results: Emodin could inhibit E2-induced MCF-7 cell proliferation and anti-apoptosis effects, and arrest the cell cycle in G0/G1 phase, further blocking the effect of E2 on expression and transcriptional activity of $ER{\alpha}$. Moreover, Emodin influenced the ER ${\alpha}$ genomic pathway via downregulation of cyclin D1 and Bcl-2 protein expression, and influenced the non-genomic pathway via decreased PI3K/Akt protein expression. Conclusions: These findings indicate that emodin exerts inhibitory effects on MCF-7 cell proliferation via inhibiting both non-genomic and genomic pathways.

• Molecules and Cells
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• v.20 no.3
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• pp.378-384
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• 2005

Estrogen metabolites are carcinogenic. The comparative mitogenic activities of $17{\beta}$-estradiol (E2) and four metabolites, 2-hydroxyestradiol (2-OHE2), 4-hydroxyestradiol (4-OHE2), $16{\alpha}$-hydroxyestrone ($16{\alpha}$-OHE1) and 2-methoxyestradiol (2-ME), were determined in estrogen receptor(ER)-positive MCF-7 human breast cancer cells. Each of the E2 metabolites caused proliferation of the MCF-7 cells, but only E2 and $16{\alpha}$-OHE1 induced a greater than 20-fold increases in transcripts of the progesterone receptor (PR) gene, a classical ER-mediated gene. This suggests that the mitogenic action of E2 and $16{\alpha}$-OHE1 could result from their effects on gene expression via the ER. E2 metabolites altered the expression of E2-regulated proteins including heat shock proteins (Hsps). $16{\alpha}$-OHE1 and 2-ME as well as E2 increased levels of Hsp56, Hsp60, $Hsp90{\alpha}$ and Hsp110 transcripts, and the patterns of these inductions resembled that of PR. Hsp56 and Hsp60 protein levels were increased by all the E2 metabolites. Levels of the transcripts of 3 E2-upregulated proteins (XTP3-transactivated protein A, protein disulfide isomerase-associated 4 protein and stathmin 1) and an E2-downregulated protein (aminoacylase 1) were also affected by the E2 metabolites. These results suggest that the altered expression of Hsps (especially Hsp56 and Hsp60) by E2 metabolites such as E2, $16{\alpha}$-OHE1 and 2-ME could be closely linked to their mitogenic action.

• 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.

• Journal of Life Science
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• v.19 no.5
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• pp.593-597
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• 2009

The uterus plays a critical role in pregnancy and steroid hormones, and both estrogen (E2) and progesterone (P4) especially play important roles in the cross-talk between embryos and uterus to support the pregnancy. E2 stimulates uterine growth during early pregnancy to prepare for implantation of embryos. This cross-talk during the implantation period involves hormones (E2 and P4) and growth factors, including insulin-like growth factor-I (IGF-I). In the uterus of a pregnant pig, the action of E2 is mediated by estrogen receptor-${\beta}$ (ER-${\beta}$). The expression of ER-a was much higher in early pregnancy than in mid- and late- pregnancy, suggesting E2 secretion from embryos enhances transcription of ER-a during early pregnancy. In order to prove whether IGF-I is an E2 target gene, quantitative real-time PCR was performed on ovariectomized murine uterus with E2 and/or P4 treatment(s). Increased IGF-I mRNA expression was observed with E2 treatment, however, it was not significantly induced by P4 treatment, which clearly demonstrates that, in mice, E2 depends on the activation of uterine IGF-I gene expression. The expression of IGF-I in the uterus of pigs was much higher in early pregnancy than in mid- and late- pregnancy and these data exhibited the same expression pattern with the ER-${\beta}$ gene expression in the uterus. It suggests that a positive co-relationship between IGF-I and ER-${\beta}$ expression exists in the uterus, and that both gene expressions of IGF-I and ER-${\beta}$ are regulated by E2. It further suggests that uterine the IGF-I gene expression might be initiated by E2 secreted from embryos to increase ER-${\beta}$ gene expression, and that this increased ER-${\beta}$ further stimulates the expression of IGF-I in the uterus during early pregnancy.

• Genomics & Informatics
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• v.18 no.4
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• pp.35.1-35.7
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• 2020

Identifying the patterns of gene expression in breast cancers is essential to understanding their pathophysiology and developing anticancer drugs. Breast cancer is a heterogeneous disease with different subtypes determined by distinct biological features. Luminal breast cancer is characterized by a relatively high expression of estrogen receptor (ER) and progesterone receptor (PR) genes, which are expressed in breast luminal cells. In ~25% of invasive breast cancers, human epidermal growth factor receptor 2 (HER2) is overexpressed; these cancers are categorized as the HER2 type. Triple-negative breast cancer (TNBC), in which the cancer cells do not express ER/PR or HER2, shows highly aggressive clinical outcomes. TNBC can be further classified into specific subtypes according to genomic mutations and cancer immunogenicity. Herein, we discuss the brief history of TNBC classification and its implications for promising treatments.

• Environmental Mutagens and Carcinogens
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• v.26 no.1
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• pp.12-19
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• 2006

Cadmium, a human carcinogen, can induce toxicity in various cell lines and organs. Despite extensive research, the mechanisms of cadmium-induced cell toxicity and estrogenic potential in human are not clear. This study was performed to investigate cadmium-induced toxicity on human breast cancer cells: MCF-7 cells, an estrogen receptor (ER) positive breast cancer cells, and MDA-MB-231 cells, an ER negative breast cancer cells. MCF-7 cells was proved to be more sensitive than the other cell lines (IC50 = $50\;{\mu}M$ at MCF-7 cells and $120{\mu}M$ at MDA-MB-231). The expression of JNK and AP-1 transcription factors such as c-Jun and c-Fos dependent transcription were increased by cadmium treatment. Inhibition of ER activation by ER antagonist (tamoxifen or ICI 182,780) significantly recovered the viablity and inhibited apoptotic cell death. This suggested that cadmium-induced cell death in ER (+) cells was mediated by JNK/AP-1 pathway and this pathway was more stimulated by ER activated by cadmium. Co-treatment of antioxidants such as selenium (Se), butylated hydroxyanisole (BHA), glutathione (GSH), or N-acetyl-L-cysteine (NAC) recovered the cadmium-induced cell death in MCF-7 cells. Cadmium-induced lipid peroxidation was decreased by GSH, NAC, or BHA in MCF-7 cells. The expression of SOD protein was decreased by cadmium ($100{\mu}M$) but recovered by GSH, NAC, BHA, or Se. Our data showed that the cadmium-induced cell toxicity in human breast cancer cells could be protected by the antioxidants (Se, BHA, NAC, GSH, or NAC) and ER antagonist (tamoxifen or ICI 182,780). Therefore, toxicity of cadmium in breast cancer were mediated by oxidative stress and $ER{\alpha}$.