• BMB Reports
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• 제44권10호
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• pp.613-618
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• 2011

Two key molecules in skeletal tissues are bone formation master transcription factor Runx2 and the steroid hormone estrogen. It is well known that these two molecules play pivotal roles in bone homeostasis; however, the functional interaction between Runx2 and estrogen synthesis in skeletal tissues is largely unknown. Recent studies have indicated that there is a positive relationship between Runx2 and the estrogen biosynthesis pathway. In this review, a possible functional link between Runx2 and estrogen synthesis pathway in skeletal tissues will be discusses as well as the biological significance of this interaction.

• BMB Reports
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• 제44권7호
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• pp.423-434
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• 2011

A female hormone, estrogen, is linked to breast cancer incidence. Estrogens undergo phase I and II metabolism by which they are biotransformed into genotoxic catechol estrogen metabolites and conjugate metabolites are produced for excretion or accumulation. The molecular mechanisms underlying estrogen-mediated mammary carcinogenesis remain unclear. Cell proliferation through activation of estrogen receptor (ER) by its agonist ligands and is clearly considered as one of carcinogenic mechanisms. Recent studies have proposed that reactive oxygen species generated from estrogen or estrogen metabolites are attributed to genotoxic effects and signal transduction through influencing redox sensitive transcription factors resulting in cell transformation, cell cycle, migration, and invasion of the breast cancer. Conjuguation metabolic pathway is thought to protect cells from genotoxic and cytotoxic effects by catechol estrogen metabolites. However, methoxylated catechol estrogens have been shown to induce ER-mediated signaling pathways, implying that conjugation is not a simply detoxification pathway. Dual action of catechol estrogen metabolites in mammary carcinogenesis as the ER-signaling molecules and chemical carcinogen will be discussed in this review.

• 생명과학회지
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• 제32권11호
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• pp.882-889
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• 2022

Breast cancer anti-estrogen resistance 3 (BCAR3)는 유방암에서 항에스트로겐 내성을 유도하는 유전자들 중의 하나로 발견되었다. 우리는 이미 BCAR3가 c-jun, activator protein-1, serum response element의 promoter 등을 활성화하는 것을 보고하였다. 본 연구에서 우리는 정상 유방세포인 MCF-12A에서 estrogen response element (ERE) 활성에서의 BCAR3의 기능을 조사하였다. BCAR3의 발현이 ERE를 활성화하는 것을 발견하였다. 이 ERE 활성화는 17β-estradiol에 의해 더욱 증가하였고, 이는 항에스트론겐인 tamoxifen에 의해 억제되지 않았다. 다음으로 우리는 ERE 활성화를 이끄는 BCAR3의 신호전달 경로를 연구하였다. BCAR3에 의한 ERE 활성화는 phosphatidylinositol (PI) 3-kinase 경로 억제제인 LY294002와 AZD5363에 의해서는 억제되었으나, Mitogen-activated protein kinase 경로 억제제인 PD98059와 U0126에 의해서는 억제되지 않았다. ERE 활성화는 PI3-kinase의 catalytic subunit p110α와 Akt의 active mutant에 의해서는 유도되었고, 이 활성화는 추가적인 BCAR3에 의해서는 더욱 증가하지 않았다. 이러한 결과로부터 우리는 BCAR3가 PI3-kinase/Akt 신호전달경로를 통하여 ERE 활성화에 중요한 역할을 하는 것을 제시한다.

• Molecules and Cells
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• 제27권3호
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• pp.351-357
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• 2009

Phytoestrogens are the natural compounds isolated from plants, which are structurally similar to animal estrogen, $17{\beta}$-estradiol. Tectoridin, a major isoflavone isolated from the rhizome of Belamcanda chinensis. Tectoridin is known as a phytoestrogen, however, the molecular mechanisms underlying its estrogenic effect are remained unclear. In this study we investigated the estrogenic signaling triggered by tectoridin as compared to a famous phytoestrogen, genistein in MCF-7 human breast cancer cells. Tectoridin scarcely binds to ER ${\alpha}$ as compared to $17{\beta}$-estradiol and genistein. Despite poor binding to ER ${\alpha}$, tectoridin induced potent estrogenic effects, namely recovery of the population of cells in the S-phase after serum starvation, transactivation of the estrogen response element, and induction of MCF-7 cell proliferation. The tectoridin-induced estrogenic effect was severely abrogated by treatment with U0126, a specific MEK1/2 inhibitor. Tectoridin promoted phosphorylation of ERK1/2, but did not affect phosphorylation of ER ${\alpha}$ at $Ser^{118}$. It also increased cellular accumulation of cAMP, a hallmark of GPR30-mediated estrogen signaling. These data imply that tectoridin exerts its estrogenic effect mainly via the GPR30 and ERK-mediated rapid nongenomic estrogen signaling pathway. This property of tectoridin sets it aside from genistein where it exerts the estrogenic effects via both an ER-dependent genomic pathway and a GPR30-dependent nongenomic pathway.

• Preventive Nutrition and Food Science
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• 제12권4호
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• pp.197-201
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• 2007

Genistein is an active component of legumes and other related food shown to be associated with prevention of degenerative diseases such as cancer through inducing signaling pathways. Treatment of genistein resulted in the induction of apoptosis in the cultured cancer cells. This induction of apoptosis was demonstrated by the Tunel assay in these cells. Unveiling the potential of genistein in cytotoxicity via apoptosis when it is treated with estrogen can predict the therapeutic capability of genistein in breast cancers in the presence of endogenous estrogen. We have found that apoptosis induced by genistein treatment in the presence of estrogen is agonistic or antagonistic depending on the concentrations and treatment periods applied in MCF-7 breast cancer cells. For the suppression of cell survival, 24 hr of treatment was required to induce a synergistic agonistic response between estrogen and genistein at low concentrations of genistein. After this period, the agonistic pattern of genistein to estrogen disappeared. The decrement of COX-2 expression in MCF-7 cells treated with genistein was accompanied with the activation of AMPK only at a high concentration of genistein. This association between AMPK activation and down-regulation of COX-2 by genistein was dampened in the presence of estrogen. It was also demonstrated that genistein and estrogen regulate cell survival and apoptosis by modulating p53 and caspase-3 in the opposite direction. These results suggest that genistein has the potential to control breast cancer development, and co-treatment with estrogen can cause agonistic or antagonistic action on breast cancer cell control.

• Archives of Pharmacal Research
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• 제29권5호
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• pp.354-362
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• 2006

Dietary flavonoids have attracted a great deal of attention as agents for preventing estrogen-related diseases, such as postmenopausal symptoms, and for reducing the risk of estrogen-dependent cancer. Kaempferol is one of the most commonly found dietary phytoestrogen. The aim of this study was to investigate the estrogenic and/or antiestrogenic effect of kaempferol, which can confirm its potency as a preventive agent against estrogen-related diseases. Kaempferol has both estrogenic and antiestrogenic activity, which are biphasic response on estrogen receptor. The estrogenic activity of kaempferol induced via ER-mediated pathway depending on $E_2$ concentration $(\leq\;10^{-12}M)$. Kaempferol $(10^{-5}\;M)$ also caused antiproliferative effect on MCF-7 cell in the presence of $E_2\;(10^{-11}\;M)$ and restored to the addition of excess $E_2\;(10^{-7}\;M)$, which confirms that antiproliferation of kaempferol was induced via ER-dependent pathway. However, at $10^{-4}\;M$, concentration higher than the concentrations at which the estrogenic effects of kaempferol are detected $(10^{-5}\;M)$, kaempferol induced strong antiproliferative effect, but were unaffected by the addition of excess $E_2\;(10^{-7}\;M)$ indicating that kaempferol exerts antiproliferation via ER-independent pathway. In particular, kaempferol blocked the focus formation induced by $E_2$, which confirms that kaempferol might inhibit the malignant transformation caused by estrogens. Therefore, we suggested that kaempferol might regulate a suitable level of estrogenic activity in the body and is expected to have potential beneficial effects in preventing estrogen imbalance diseases (breast cancer, osteoporosis, cardiovascular disease and etc.).

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 2003년도 Annual Meeting of KSAP : International Symposium on Pharmaceutical and Biomedical Sciences on Obesity
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• pp.70-70
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• 2003

Estrogen receptor is a ligand-activated transcription factor. Its action depends on the receptor, its ligand, and its coactivator proteins. As a consequence, the concentration of the receptor is a major component that governs the magnitude of the estrogen response. Despite the extensive knowledge on mechanism of estrogen receptor action, regulation of estrogen receptor itself is not very well understood. Estrogen receptor is known to be downregulated under hypoxia leading to inhibition of estrogen receptor mediated transcription activation. We have studied mechanism of loss of estrogen responsiveness under hypoxia. We found that Hif-l${\alpha}$, a major transcription factor regulating hypoxic response, inhibited transcription of estrogen response element driven luciferase gene by expression of HIF-l${\alpha}$/vp16 construct designed to contain transcription activity under normoxia. This loss of estrogen responsiveness appears to be the result of ER${\alpha}$ downregulation. ER${\alpha}$was downregulated at the levels of ligand-biding and protein within l2-24h, and the response was blocked by the proteasome inhibitor MG132, protein synthesis inhibitor cyclohexamide, and tyrosine kinase inhibitor Genistein. These results demonstrate that Hif-l${\alpha}$ downregulates ER${\alpha}$ by proteasome dependent pathway.

• BMB Reports
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• 제42권8호
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• pp.516-522
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• 2009

SH2D4A, comprising a single SH2 domain, is a novel protein of the SH2 signaling protein family. We have previously demonstrated SH2D4A is expressed ubiquitously in various tissues and is located in the cytoplasm. In this study we investigated the function of SH2D4A in human embryonic kidney (HEK) 293 cells using interaction analysis, cell proliferation assays, and kinase activity detection. SH2D4A was found to directly bind to estrogen receptor $\alpha$ (ER$\alpha$), and prevent the recruitment of phospholipase C-$\gamma$ (PLC-$\gamma$) to ER$\alpha$. Moreover, we observed its inhibitory effects on estrogen-induced cell proliferation, involving the protein kinase C (PKC) signaling pathway. Together, these findings suggested that SH2D4A inhibited cell proliferation by suppression of the ER$\alpha$/PLC-$\gamma$/PKC signaling pathway. SH2D4A may be useful for the development of a new anti-cancer drug acting as an ER signaling modulator.

• 한국발생생물학회지:발생과생식
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• 제22권1호
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• pp.95-104
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• 2018

CREBZF (cAMP-response element binding protein zhangfei) is a member of ATF/CREB family, and which regulates various cellular functions by suppressing major factors with direct interaction. In this study, we have examined the expression of CREBZF on mouse endometrium during uterus estrous cycles and estrogen (E2) treatment. In uterus, CREBZF mRNA expression was higher than other organs and mRNA and protein of CREBZF was increased in proestrus phase and decreased in estrus phase. The expression of CREBZF in 3-weeks old mouse uterus was reduced by E2 injection in endometrium. In addition, the expression of progesterone receptor, a marker of E2 in ovariectomized mice was found to be strongly expressed in stroma, while CREBZF was only expressed in epithelium. Also, we conformed that E2-suppressed CREBZF was restored by co-injection of ICI 182,780, an estrogen receptor antagonist. Overall, these results suggest that CREBZF is regulated by estrogen and involved in ER signaling pathway in mouse uterus.

• Archives of Pharmacal Research
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• 제27권5호
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• pp.554-561
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• 2004

Trichostatin A, an antifungal antibiotics, and HC-toxin are potent and specific inhibitors of histone deacetylase activity. Histone deacetylase inhibitors are new class of chemotherapeutic drugs able to induce tumor cell apoptosis and/or cell cycle arrest. In this study, the antiproliferative activities of trichostatin A and HC-toxin were compared between estrogen receptor positive human breast cancer cell MCF-7 and estrogen receptor negative human breast cancer cell MDA-MB-468. Trichostatin A and HC-toxin showed potent antiproliferative activity in both MCF-7 and MDA-MB-468 cells. In MCF-7 cells that contain high level estrogen receptor, trichostatin A and HC-toxin brought about three-times more potent cell growth inhibitory effect than estrogen receptor negative MDA-MB-468 cells. Both trichostatin A and HC-toxin showed cell cycle arrest at G$_2$/M phases of MCF-7 and MDA-MB-468 cells in a dose- and time- depen- dent manner. Trichostatin A and HC-toxin also induced apoptosis from MCF-7 and MDA-MB-468 cells in a dose- and time-dependent manner. Results of this study suggested that antipro-liferative effects of trichostatin A and HC-toxin might be involved in estrogen receptor signaling pathway, but cell cycle arrest and apoptosis of trichostatin A and HC-toxin might not be involved in estrogen receptor system of human breast cancer cells.