Phytoestrogens Induce Differential Estrogen Receptor Alpha- or Beta-Mediated Responses in Transfected Breast Cancer Cells

2005 ◽  
Vol 230 (8) ◽  
pp. 558-568 ◽  
Author(s):  
D. M. Harris ◽  
E. Besselink ◽  
S. M. Henning ◽  
V. L. W. Go ◽  
D. Heber
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Estrogen Receptor Alpha ◽  
Estrogenic Activity ◽  
Mammary Adenocarcinoma ◽  
Luciferase Reporter ◽  
Luciferase Reporter Gene ◽  
Human Estrogen Receptor ◽  
17Β Estradiol ◽  
Risk Of Cancer

Increased intake of phytoestrogens may be associated with a lower risk of cancer in the breast and several other sites, although there is controversy surrounding this activity. One of the mechanisms proposed to explain the activity of phytoestrogens is their ability to bind and activate human estrogen receptor a (ERα) and human estrogen receptor β (ERβ). Nine phytoestrogens were tested for their ability to transactivate ERα or ERβ at a range of doses. Mammary adenocarcinoma (MCF-7) cells were co-transfected with either ERα or ERβ, and an estrogen-response element was linked to a luciferase reporter gene. Dose-dependent responses were compared with the endogenous ligand 17β-estradiol. Purified genistein, daidzein, apigenin, and coumestrol showed differential and robust transactivation of ERα- and ERβ-induced transcription, with an up to 100-fold stronger activation of ERβ. Equol, naringenin, and kaempferol were weaker agonists. When activity was evaluated against a background of 0.5 nM 17β-estradiol, the addition of genistein, daidzein, and resveratrol superstimulated the system, while kaempferol and quercetin were antagonists at the highest doses. This transfection assay provides an excellent model to evaluate the activation of ERα and ERβ by different phytoestrogens in a breast cancer context and can be used as a screening bioassay tool to evaluate the estrogenic activity of extracts of herbs and foods.

Boron clusters for medicinal drug design: Selective estrogen receptor modulators bearing carborane

2003 ◽  
Vol 75 (9) ◽  
pp. 1197-1205 ◽  
Author(s):  
Yasuyuki Endo ◽  
Tomohiro Yoshimi ◽  
Chisato Miyaura
Keyword(s):  
Estrogen Receptor ◽  
Estrogenic Activity ◽  
Medical Application ◽  
Molecular Shape ◽  
Biologically Active ◽  
Luciferase Reporter ◽  
Luciferase Reporter Gene ◽  
Estrogen Receptor Modulators ◽  
Gene Assay

The molecular shape and hydrophobicity of dicarba-closo -dodecaboranes may allow a new medical application as biologically active molecules. Recently, we have developed potent estrogen receptor (ER) agonists bearing carborane cage. The most potent compound (BE120) exhibited activity at least several times greater than that of 17 beta-estradiol in luciferase reporter gene assay and ER alpha binding. We also designed and synthesized estrogen antagonists on the basis of the structure of BE120, and we noticed the characteristic features of compound (BE360) having carborane cage and two phenols. The ER binding affinity of BE360 is comparable to that of estradiol. To examine in vivo estrogenic activity of the compound in bone, ovariectomized (OVX) mice were given BE360 or estradiol subcutaneously for 4 weeks. Treatment with BE360 at 1–30 µg/day dose-dependently restored bone loss in OVX mice to sham level without estrogenic action in uterus. These results suggest its possible application to osteoporosis as a new type of selective ER modulator.

scholarly journals Selective Activation of Estrogen Receptor-β Target Genes by 3,3′-Diindolylmethane

Endocrinology ◽  
2010 ◽  
Vol 151 (4) ◽  
pp. 1662-1667 ◽  
Author(s):  
Omar I. Vivar ◽  
Elise F. Saunier ◽  
Dale C. Leitman ◽  
Gary L. Firestone ◽  
Leonard F. Bjeldanes
Keyword(s):  
Estrogen Receptor ◽  
Transcriptional Activation ◽  
Target Genes ◽  
Estrogenic Activity ◽  
Regulatory Elements ◽  
Luciferase Reporter ◽  
Luciferase Reporter Gene ◽  
Subtype Selectivity ◽  
Estrogen Response ◽  
Endogenous Genes

3,3′-Diindolylmethane (DIM) is a natural compound found in cruciferous vegetables that has antiproliferative and estrogenic activity. However, it is not clear whether the estrogenic effects are mediated through estrogen receptor (ER)α, ERβ, or both ER subtypes. We investigated whether DIM has ER subtype selectivity on gene transcription. DIM stimulated ERβ but not ERα activation of an estrogen response element upstream of the luciferase reporter gene. DIM also selectively activated multiple endogenous genes through ERβ. DIM did not bind to ERβ, indicating that it activates genes by a ligand-independent mechanism. DIM causes ERβ to bind regulatory elements and recruit the steroid receptor coactivator (SRC)-2 coactivator, which leads to the activation of ER target genes. Silencing of SRC-2 inhibited the activation of ER target genes, demonstrating that SRC-2 is required for transcriptional activation by DIM. Our results demonstrate that DIM is a new class of ERβ-selective compounds, because it does not bind to ERβ, but instead it selectively recruits ERβ and coactivators to target genes.

scholarly journals In vitro modulation of estrogen receptor activity by norfluoxetine

2015 ◽  
Vol 88 (3) ◽  
pp. 386-390 ◽  
Author(s):  
Diana Lupu ◽  
Anca Pop ◽  
Julien Cherfan ◽  
Béla Kiss ◽  
Felicia Loghin
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptors ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Estrogenic Activity ◽  
Luciferase Reporter ◽  
Luciferase Reporter Gene ◽  
Luciferase Reporter Construct ◽  
Estrogenic Effects ◽  
Pregnancy And Postpartum

Background & Aims: Selective serotonin reuptake inhibitors (SSRIs) are antidepressants increasingly prescribed for pregnancy and postpartum depression. However, these compounds can cross the placenta and also pass into breast milk, thus reaching the fetus and infant during critical developmental stages, potentially causing adverse effects. Fluoxetine, a widely used SSRI, has been shown to affect (neuro)endocrine signaling in various organisms, including humans. This compound can also interact with estrogen receptors in vitro and cause an estrogen-dependent uterotrophic response in rodents. Consequently, the aim of the present study was to assess if the active metabolite of fluoxetine, namely norfluoxetine, shares the same capacity for estrogen receptor interaction.Materials and methods: The in vitro (anti)estrogenic activity of norfluoxetine was assessed using a firefly luciferase reporter construct in the T47D-Kbluc breast cancer cell line. These cells express nuclear estrogen receptors (ERs) that can activate the transcription of the luciferase reporter gene upon binding of ER agonists. Light emission was monitored in case of cells exposed to norfluoxetine or mixtures of norfluoxetine-estradiol. Cell viability was assessed using a resazurin-based assay.Results: During individual testing, NFLX was able to induce a significant increase in luciferase activity compared to control, but only at the highest concentration tested (10 µM). In binary mixtures with estradiol (30pM constant concentration) a significant increase in luminescence was observed at low submicromolar norfluoxetine concentrations compared to estradiol alone.Conclusion: Norfluoxetine can induce estrogenic effects in vitro and can potentiate the activity of estradiol. However, further studies are needed to clarify if these observed estrogenic effects may have detrimental consequences for human exposure.

scholarly journals Estrogenic/antiestrogenic activity of selected selective serotonin reuptake inhibitors

2015 ◽  
Vol 88 (3) ◽  
pp. 381-385 ◽  
Author(s):  
Anca Pop ◽  
Diana Ioana Lupu ◽  
Julien Cherfan ◽  
Bela Kiss ◽  
Felicia Loghin
Keyword(s):  
Estrogen Receptor ◽  
Serotonin Reuptake ◽  
Transcriptional Activity ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Estrogenic Activity ◽  
Serotonin Reuptake Inhibitors ◽  
Selective Serotonin ◽  
Luciferase Reporter ◽  
Luciferase Reporter Gene ◽  
Luciferase Reporter Construct

Backround & Aims: Selective serotonin reuptake inhibitors (SSRIs) are one of the most prescribed classes of psychotropics. Even though the SSRI class consists of 6 molecules (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline), only fluoxetine was intensively studied for endocrine disruptive effects, while the other SSRIs received less attention. This study was designed to evaluate the estrogenic/antiestrogenic effect of fluoxetine, sertraline and paroxetine.Materials and methods: The in vitro (anti)estrogenic activity was assessed using a firefly luciferase reporter construct in the T47D-KBluc breast cancer cell line. These cells express nuclear estrogen receptors that can activate the transcription of the luciferase reporter gene upon binding of estrogen receptor agonists.  Results: All three compounds were found to interact with the estrogen receptor. Fluoxetine had dual properties, weak estrogenic at lower concentrations and antiestrogenic effect at higher concentrations. Sertraline shared the same properties with fluoxetine, but also increased the estradiol-mediated transcriptional activity. Paroxetine presented only one type of effect, the ability to increase the estradiol-mediated transcriptional activity. Conclusions: Overall, our results indicate a possible interaction of SSRIs with the estrogen receptor. As SSRIs are being used by all categories of population, including pregnant women or children, establishing whether they can affect the endocrine mediated mechanisms should be a priority.

scholarly journals 17β-estradiol regulates giant vesicle formation via estrogen receptor-alpha in human breast cancer cells

Oncotarget ◽  
2014 ◽  
Vol 5 (10) ◽  
pp. 3055-3065 ◽  
Author(s):  
Paul K Wright ◽  
Sarah Bowen Jones ◽  
Nicholas Ardern ◽  
Rebecca Ward ◽  
Robert B Clarke ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Estrogen Receptor Alpha ◽  
Vesicle Formation ◽  
Human Breast Cancer Cells ◽  
Human Breast ◽  
17Β Estradiol
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