scholarly journals Estrogen receptor α regulates the expression of syndecan-1 in human breast carcinoma cells

2019 ◽  
Vol 26 (6) ◽  
pp. 615-628 ◽  
Author(s):  
Emmanuelle Fleurot ◽  
Caroline Goudin ◽  
Vincent Hanoux ◽  
Pierre-Jacques Bonnamy ◽  
Jérôme Levallet
Keyword(s):  
Estrogen Receptor ◽  
De Novo ◽  
Acquired Resistance ◽  
Inverse Correlation ◽  
Estrogen Receptor Α ◽  
Mcf7 Cells ◽  
Irreversible Inhibitor ◽  
Attractive Therapeutic Target ◽  
Antihormonal Therapy ◽  
Er Expression

Breast cancer (BC) is the primary cause of cancer-related mortality among women. Patients who express the estrogen receptor (ER), which mediates the tumorigenic effects of estrogens, respond to antihormonal therapy. Loss of ER expression or acquired resistance to E2 is associated with aggressive malignant phenotypes, which lead to relapse. These BC subtypes overexpress syndecan-1 (SDC1), a transmembrane heparan sulfate proteoglycan that mediates angiogenesis as well as the proliferation and invasiveness of cancer cells. We showed here that the activation of ER-alpha (ERα) by estrogens induces downregulation of SDC1 expression in ER(+) MCF7 cells but not in T47D cells. Loss of ERα expression, induced by RNA interference or a selective ER downregulator, led to subsequent SDC1 overexpression. E2-dependent downregulation of SDC1 expression required de novo protein synthesis and was antagonized by treatment with BAY 11-7085, an irreversible inhibitor of IκBα phosphorylation, which inhibits the activation of NFκB. Downregulation of SDC1 expression required ERα and activation of IKK, but was independent to downstream transcriptional regulators of NFκB. BAY 11-7085 prevented E2-mediated phosphorylation of ERα on Ser118, increasing its proteasomal degradation, suggesting that IKK stabilized E2-activated ERα, leading to subsequent downregulation of SDC1 expression. Our results showed that sustained ER signaling inhibits SDC1 expression. Such antagonism elucidates the inverse correlation between SDC1 and ER expression in ER(+) BC as well as the overexpression of SDC1 in hormone receptor-negative BC subtypes with the most aggressive phenotypes. These results identify SDC1 as an attractive therapeutic target for BC as well as for other endocrine-associated cancers.

scholarly journals Transcriptome analysis and connectivity mapping of Cissampelos pareira L. provides molecular links of ESR1 modulation to viral inhibition

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Madiha Haider ◽  
Dhwani Dholakia ◽  
Aleksha Panwar ◽  
Parth Garg ◽  
Atish Gheware ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Mcf7 Cell ◽  
Estrogen Receptor Α ◽  
Viral Inhibition ◽  
Mcf7 Cells ◽  
Docking Analysis ◽  
Female Hormone ◽  
Herbal Formulation ◽  
Estrogen Response ◽  
Estrogen Receptor 1

AbstractBioactive fractions obtained from medicinal plants which have been used for the treatment of multiple diseases could exert their effects by targeting common pathways. Prior knowledge of their usage could allow us to identify novel molecular links. In this study, we explored the molecular basis of action of one such herbal formulation Cissampelos pareira L. (Cipa), used for the treatment of female hormone disorders and fever. Transcriptomic studies on MCF7 cell lines treated with Cipa extract carried out using Affymetrix arrays revealed a downregulation of signatures of estrogen response potentially modulated through estrogen receptor α (ERα). Molecular docking analysis identified 38 Cipa constituents that potentially bind (ΔG <  − 7.5) with ERα at the same site as estrogen. The expression signatures in the connectivity map (https://clue.io/;) revealed high positive scores with translation inhibitors such as emetine (score: 99.61) and knockdown signatures of genes linked to the antiviral response such as ribosomal protein RPL7 (score: 99.92), which is a reported ERα coactivator. Further, gene knockdown experiments revealed that Cipa exhibits antiviral activity in dengue infected MCF7 cells potentially modulated through estrogen receptor 1. This approach reveals a novel pathway involving the ESR1-RPL7 axis which could be a potential target in dengue viral infection.

scholarly journals The Human Estrogen Receptor-α Isoform hERα46 Antagonizes the Proliferative Influence of hERα66 in MCF7 Breast Cancer Cells

Endocrinology ◽  
2005 ◽  
Vol 146 (12) ◽  
pp. 5474-5484 ◽  
Author(s):  
Graziella Penot ◽  
Christine Le Péron ◽  
Yohann Mérot ◽  
Eva Grimaud-Fanouillère ◽  
François Ferrière ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Estrogen Receptor ◽  
Cell Growth ◽  
Activation Function ◽  
Estrogen Receptor Α ◽  
Breast Cancer Cell Lines ◽  
Mcf7 Cells ◽  
Exact Function ◽  
Human Estrogen Receptor

The expression of two human estrogen receptor-α (hERα) isoforms has been characterized within estrogen receptor-α-positive breast cancer cell lines such as MCF7: the full-length hERα66 and the N terminally deleted hERα46, which is devoid of activation function (AF)-1. Although hERα66 is known to mediate the mitogenic effects that estrogens have on MCF7 cells, the exact function of hERα46 in these cells remains undefined. Here we show that, during MCF7 cell growth, hERα46 is mainly expressed in the nucleus at relatively low levels, whereas hERα66 accumulates in the nucleus. When cells reach confluence, the situation reverses, with hERα46 accumulating within the nucleus. Although hERα46 expression remains rather stable during an estrogen-induced cell cycle, its overexpression in proliferating MCF7 cells provokes a cell-cycle arrest in G0/G1 phases. To gain further details on the influence of hERα46 on cell growth, we used PC12 estrogen receptor-α-negative cell line, in which stable transfection of hERα66 but not hERα46 allows estrogens to behave as mitogens. We next demonstrate that, in MCF7 cells, overexpression of hERα46 inhibits the hERα66-mediated estrogenic induction of all AF-1-sensitive reporters: c-fos and cyclin D1 as well as estrogen-responsive element-driven reporters. Our data indicate that this inhibition occurs likely through functional competitions between both isoforms. In summary, hERα46 antagonizes the proliferative action of hERα66 in MCF7 cells in part by inhibiting hERα66 AF-1 activity.

scholarly journals Monitoring the Crosstalk Between the Estrogen Receptor and Human Epidermal Growth Factor Receptor 2 with PET

2020 ◽  
Vol 22 (5) ◽  
pp. 1218-1225
Author(s):  
I. F. Antunes ◽  
G. A. P. Hospers ◽  
J. W. A. Sijbesma ◽  
A. S. Boerema ◽  
A. van Waarde ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Estrogen Receptor ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Ex Vivo ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Targeted Treatment ◽  
Epidermal Growth ◽  
Er Expression

Abstract Purpose Ovarian cancer (OC) leads to poor survival rates mainly due to late stage detection and innate or acquired resistance to chemotherapy. Thus, efforts have been made to exploit the estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) to treat OC. However, patients eventually become resistant to these treatments as well. HER2 overexpression contributes to the acquired resistance to ER-targeted treatment. Trastuzumab treatment, on the other hand, can result in increased expression of ER, which, in turn, increases the sensitivity of the tumors towards anti-estrogen therapy. More insight into the crosstalk between ER and HER2 signaling could improve our knowledge about acquired resistance in ovarian cancer. The aim of this study was to evaluate whether PET could be used to detect changes in ER expression induced by HER2-targeted treatment in vivo. Procedures Male athymic nude mice were subcutaneously (sc) inoculated with 106 SKOV3 human ovarian cancer cells (HER2+/ER+). Two weeks after inoculation, tumor-bearing mice were treated intraperitoneally with either vehicle, the HER2 antibody trastuzumab (20 mg/kg, 2×/week), or the HER2-tyrosine kinase inhibitor lapatinib (40 mg/kg, 5 days/week) for 2 weeks. Thereafter, ER expression in the tumor was assessed by PET imaging with 16α-[18F]-fluoro-17β-estradiol ([18F]FES). Tumors were excised for ex vivo ER and HER2 measurement with Western blotting and immunohistochemistry. Results All treatments led to smaller tumors than vehicle-treated tumors. Higher [18F]FES maximum standardize tumor uptake (SUVmax) was observed in animals treated with trastuzumab (+ 29 %, P = 0.002) or lapatinib (+ 20 %, P = 0.096) than in vehicle-treated controls. PET results were in agreement with ex vivo analyses. Conclusion FES-PET imaging can detect changes in ER expression induced by HER2-targeted treatment and therefore can be used to investigate the crosstalk between ER and HER2 in a noninvasive manner.

scholarly journals Identification and Analysis of Estrogen Receptor α Promoting Tamoxifen Resistance-Related lncRNAs

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Xiulei Zhang ◽  
Shanjun Gao ◽  
Zhen Li ◽  
Wei Wang ◽  
Guangzhi Liu
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Patients ◽  
Estrogen Receptor Alpha ◽  
Acquired Resistance ◽  
Tamoxifen Resistance ◽  
Estrogen Receptor Α ◽  
Rna Seq ◽  
Breast Cancer Patients ◽  
Mcf 7

70-75% breast cancer patients are estrogen receptor alpha positive (ERα+), and the antiestrogen drug tamoxifen has been used for the past three decades. However, in 20-30% of these patients, tamoxifen therapy fails due to intrinsic or acquired resistance. A previous study has showed ERα signaling still exerts significant roles in the development of tamoxifen resistance and several lncRNAs have been demonstrated important roles in tamoxifen resistance. But ERα directly regulated and tamoxifen resistance related lncRNAs remain to be discovered. We reanalyze the published ERα chromatin immunoprecipitation-seq (ChIP-seq) and RNA-seq data of tamoxifen-sensitive (MCF-7/WT) and tamoxifen-resistant (MCF-7/TamR) breast cancer cells. We demonstrate that there are differential ERα recruitment events and the differentials may alert the expression profile in MCF-7/WT and MCF-7/TamR cells. Furthermore, we make an overlap of the ERα binding lncRNAs and differentially expressed lncRNAs and get 49 ERα positively regulated lncRNAs. Among these lncRNAs, the expression levels of AC117383.1, AC144450.1, RP11-15H20.6, and ATXN1-AS1 are negatively correlated with the survival probability of breast cancer patients and ELOVL2-AS1, PCOLCE-AS1, ITGA9-AS1, and FLNB-AS1 are positively correlated. These lncRNAs may be potential diagnosis or prognosis markers of tamoxifen resistance.

scholarly journals Estrogen receptor-α mediates gene expression changes and growth response in ovarian cancer cells exposed to estrogen

2005 ◽  
Vol 12 (4) ◽  
pp. 851-866 ◽  
Author(s):  
Amanda J M O’Donnell ◽  
Kenneth G Macleod ◽  
David J Burns ◽  
John F Smyth ◽  
Simon P Langdon
Keyword(s):  
Gene Expression ◽  
Ovarian Cancer ◽  
Estrogen Receptor ◽  
Ovarian Carcinoma ◽  
Significant Role ◽  
Target Genes ◽  
De Novo ◽  
Estrogen Receptor Α ◽  
Ovarian Cancer Cells ◽  
Real Time Quantitative Pcr

Estrogens play a significant role in the development, growth, invasion and metastasis of ovarian tumors. The transcriptional program regulated by 17β-estradiol (E2) in human ovarian cancer cell lines was analyzed using cDNA microarrays containing 1200 cancer-related genes. Twenty-eight transcripts had at least a threefold change in expression in E2-treated PEO1 ovarian carcinoma cells compared with controls. These differences were confirmed by real-time quantitative PCR and shown to be dependent upon the expression of functional estrogen receptor-α (ERα). Consistent with this, these gene expression changes were blocked by the anti-estrogen tamoxifen. The use of ERα- and ERβ-specific ligands allowed molecular dissection of the E2 response and showed that ERα activation was responsible for the observed changes in gene expression, whereas ERβ played no significant role. Inhibition of de novo protein synthesis by cycloheximide was used to distinguish between primary and secondary target genes regulated by E2. Actinomycin D was used to show that changes in gene expression levels induced by E2 were a result of changes in transcription and not due to changes in mRNA stability. The results presented here demonstrate that estrogen-driven growth of epithelial ovarian carcinoma is mediated by activation of ERα-mediated, and not ERβ-mediated, transcription.

scholarly journals A selective estrogen receptor α agonist ameliorates hepatic steatosis in the male aromatase knockout mouse

2011 ◽  
Vol 210 (3) ◽  
pp. 323-334 ◽  
Author(s):  
Jenny D Y Chow ◽  
Margaret E E Jones ◽  
Katja Prelle ◽  
Evan R Simpson ◽  
Wah Chin Boon
Keyword(s):  
Estrogen Receptor ◽  
Hepatic Steatosis ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Regulatory Element ◽  
Normal Liver ◽  
Transcript Level ◽  
Estrogen Receptor Α ◽  
Upstream Regulator ◽  
Male Specific

Male aromatase knockout mice (ArKO; an estrogen-deficient model) present with male-specific hepatic steatosis that is reversible upon 17β-estradiol replacement. This study aims to elucidate which estrogen receptor (ER) subtype, ERα or ERβ, is involved in the regulation of triglyceride (TG) homeostasis in the liver. Nine-month-old male ArKO mice were treated with vehicle, ERα- or ERβ-specific agonists via s.c. injection, daily for 6 weeks. Male ArKO mice treated with ERα agonist had normal liver histology and TG contents compared with vehicle-treated ArKO; omental (gonadal) and infra-renal (visceral) fat pad weights were normalized to those of vehicle-treated wild-type (WT). In contrast, ERβ agonist treatment did not result in the similar reversal of these ArKO phenotypes. In vehicle-treated ArKO mice, hepatic transcript expression of fatty acid synthase (Fasn) and stearoyl-coenzyme A desaturase 1 (key enzymes inde novoFA synthesis) were significantly elevated compared with vehicle-treated WT, but onlyFasnexpression was lowered to WT level after ERα agonist treatment. There were no significant changes in the transcript levels of carnitine palmitoyl transferase 1 (required for transfer of FA residues into the mitochondria for β-oxidation) and sterol regulatory element-binding factor 1c (the upstream regulator ofde novoFA synthesis). We also confirmed by RT-PCR that only ERα is expressed in the mouse liver. There were no changes in hepatic androgen receptor transcript level across all treatment groups. Our data suggest that estrogens act via ERα to regulate TG homeostasis in the ArKO liver. Since the liver, adipose tissue and arcuate nucleus express mainly ERα, estrogens could regulate hepatic functions via peripheral and central pathways.

scholarly journals Protein Phosphatase 2A Regulates Estrogen Receptor α (ER) Expression through Modulation of ER mRNA Stability

2005 ◽  
Vol 280 (33) ◽  
pp. 29519-29524 ◽  
Author(s):  
Judith C. Keen ◽  
Qun Zhou ◽  
Ben Ho Park ◽  
Catherine Pettit ◽  
Kelly M. Mack ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Mrna Stability ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Estrogen Receptor Α ◽  
Phosphatase 2A ◽  
Er Expression

scholarly journals Raloxifene and ICI182,780 Increase Estrogen Receptor-α Association with a Nuclear Compartment via Overlapping Sets of Hydrophobic Amino Acids in Activation Function 2 Helix 12

2007 ◽  
Vol 21 (4) ◽  
pp. 797-816 ◽  
Author(s):  
Mathieu Lupien ◽  
M. Jeyakumar ◽  
Elise Hébert ◽  
Khalid Hilmi ◽  
David Cotnoir-White ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Ligand Binding ◽  
Transcriptional Activity ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Activation Function ◽  
Estrogen Receptor Α ◽  
Mcf7 Cells ◽  
Hydrophobic Residues ◽  
Helix 12

Abstract The basis for the differential repressive effects of antiestrogens on transactivation by estrogen receptor-α (ERα) remains incompletely understood. Here, we show that the full antiestrogen ICI182,780 and, to a lesser extent, the selective ER modulator raloxifene (Ral), induce accumulation of exogenous ERα in a poorly soluble fraction in transiently transfected HepG2 or stably transfected MDA-MB231 cells and of endogenous receptor in MCF7 cells. ERα remained nuclear in HepG2 cells treated with either compound. Replacement of selected hydrophobic residues of ERα ligand-binding domain helix 12 (H12) enhanced receptor solubility in the presence of ICI182,780 or Ral. These mutations also increased transcriptional activity with Ral or ICI182,780 on reporter genes or on the endogenous estrogen target gene TFF1 in a manner requiring the integrity of the N-terminal AF-1 domain. The antiestrogen-specific effects of single mutations suggest that they affect receptor function by mechanisms other than a simple decrease in hydrophobicity of H12, possibly due to relief from local steric hindrance between these residues and the antiestrogen side chains. Fluorescence anisotropy experiments indicated an enhanced regional stabilization of mutant ligand-binding domains in the presence of antiestrogens. H12 mutations also prevent the increase in bioluminescence resonance energy transfer between ERα monomers induced by Ral or ICI182,780 and increase intranuclear receptor mobility in correlation with transcriptional activity in the presence of these antiestrogens. Our data indicate that ICI182,780 and Ral locally alter the ERα ligand binding structure via specific hydrophobic residues of H12 and decrease its transcriptional activity through tighter association with an insoluble nuclear structure.

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