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Reactivation of estrogen receptor α by vorinostat sensitizes mesenchymal-like triple-negative breast cancer to aminoflavone, a ligand of the aryl hydrocarbon receptor.

OBJECTIVEAminoflavone (AF) acts as a ligand of the aryl hydrocarbon receptor (AhR). Expression of estrogen receptor α (ERα) and AhR-mediated transcriptional induction of CYP1A1 can sensitize breast cancer cells to AF. The objective of this study was to investigate the combined antitumor effect of AF... Full description

Journal Title: PloS one 2013, Vol.8(9), p.e74525
Main Author: Stark, Karri
Other Authors: Burger, Angelika , Wu, Jianmei , Shelton, Phillip , Polin, Lisa , Li, Jing
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1932-6203 ; DOI: 10.1371/journal.pone.0074525
Link: http://search.proquest.com/docview/1435850004/?pq-origsite=primo
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title: Reactivation of estrogen receptor α by vorinostat sensitizes mesenchymal-like triple-negative breast cancer to aminoflavone, a ligand of the aryl hydrocarbon receptor.
format: Article
creator:
  • Stark, Karri
  • Burger, Angelika
  • Wu, Jianmei
  • Shelton, Phillip
  • Polin, Lisa
  • Li, Jing
subjects:
  • Animals–Drug Effects
  • Cell Line, Tumor–Drug Effects
  • Cell Proliferation–Metabolism
  • Cytoplasm–Metabolism
  • Drug Synergism–Drug Effects
  • Estrogen Receptor Alpha–Pharmacology
  • Female–Therapeutic Use
  • Flavonoids–Drug Effects
  • Fluorescent Antibody Technique–Pathology
  • Gene Expression Profiling–Metabolism
  • Gene Expression Regulation, Neoplastic–Drug Effects
  • Humans–Drug Therapy
  • Hydroxamic Acids–Genetics
  • Ligands–Metabolism
  • Mesoderm–Pathology
  • Mice–Pathology
  • Mice, Inbred Balb C–Pathology
  • Receptors, Aryl Hydrocarbon–Pathology
  • Transcription, Genetic–Pathology
  • Triple Negative Breast Neoplasms–Pathology
  • Vorinostat–Pathology
  • Xenograft Model Antitumor Assays–Pathology
  • Estrogen Receptor Alpha
  • Flavonoids
  • Hydroxamic Acids
  • Ligands
  • Receptors, Aryl Hydrocarbon
  • Estrogen Receptor Alpha, Human
  • Aminoflavone
  • Vorinostat
ispartof: PloS one, 2013, Vol.8(9), p.e74525
description: OBJECTIVEAminoflavone (AF) acts as a ligand of the aryl hydrocarbon receptor (AhR). Expression of estrogen receptor α (ERα) and AhR-mediated transcriptional induction of CYP1A1 can sensitize breast cancer cells to AF. The objective of this study was to investigate the combined antitumor effect of AF and the histone deacetylase inhibitor vorinostat for treating mesenchymal-like triple-negative breast cancer (TNBC) as well as the underlying mechanisms of such treatment. METHODSIn vitro antiproliferative activity of AFP464 (AF prodrug) in breast cancer cell lines was evaluated by MTS assay. In vitro, the combined effect of AFP464 and vorinostat on cell proliferation was assessed by the Chou-Talalay method. In vivo, antitumor activity of AFP464, given alone and in combination with vorinostat, was studied using TNBC xenograft models. Knockdown of ERα was performed using specific, small-interfering RNA. Western blot, quantitative RT-PCR, immunofluorescence, and immunohistochemical staining were performed to study the mechanisms underlying the combined antitumor effect. RESULTSLuminal and basal A subtype breast cancer cell lines were sensitive to AFP464, whereas basal B subtype or mesenchymal-like TNBC cells were resistant. Vorinostat sensitized mesenchymal-like TNBC MDA-MB-231 and Hs578T cells to AFP464. It also potentiated the antitumor activity of AFP464 in a xenograft model using MDA-MB-231 cells. In vitro and in vivo mechanistic studies suggested that vorinostat reactivated ERα expression and restored AhR-mediated transcriptional induction of CYP1A1. CONCLUSIONThe response of breast cancer cells to AF or AFP464 was associated with their gene expression profile. Vorinostat sensitized mesenchymal-like TNBC to AF, at least in part, by reactivating ERα expression and restoring the responsiveness of AhR to AF.
language: eng
source:
identifier: E-ISSN: 1932-6203 ; DOI: 10.1371/journal.pone.0074525
fulltext: fulltext
issn:
  • 19326203
  • 1932-6203
url: Link


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titleReactivation of estrogen receptor α by vorinostat sensitizes mesenchymal-like triple-negative breast cancer to aminoflavone, a ligand of the aryl hydrocarbon receptor.
creatorStark, Karri ; Burger, Angelika ; Wu, Jianmei ; Shelton, Phillip ; Polin, Lisa ; Li, Jing
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ispartofPloS one, 2013, Vol.8(9), p.e74525
identifierE-ISSN: 1932-6203 ; DOI: 10.1371/journal.pone.0074525
subjectAnimals–Drug Effects ; Cell Line, Tumor–Drug Effects ; Cell Proliferation–Metabolism ; Cytoplasm–Metabolism ; Drug Synergism–Drug Effects ; Estrogen Receptor Alpha–Pharmacology ; Female–Therapeutic Use ; Flavonoids–Drug Effects ; Fluorescent Antibody Technique–Pathology ; Gene Expression Profiling–Metabolism ; Gene Expression Regulation, Neoplastic–Drug Effects ; Humans–Drug Therapy ; Hydroxamic Acids–Genetics ; Ligands–Metabolism ; Mesoderm–Pathology ; Mice–Pathology ; Mice, Inbred Balb C–Pathology ; Receptors, Aryl Hydrocarbon–Pathology ; Transcription, Genetic–Pathology ; Triple Negative Breast Neoplasms–Pathology ; Vorinostat–Pathology ; Xenograft Model Antitumor Assays–Pathology ; Estrogen Receptor Alpha ; Flavonoids ; Hydroxamic Acids ; Ligands ; Receptors, Aryl Hydrocarbon ; Estrogen Receptor Alpha, Human ; Aminoflavone ; Vorinostat
descriptionOBJECTIVEAminoflavone (AF) acts as a ligand of the aryl hydrocarbon receptor (AhR). Expression of estrogen receptor α (ERα) and AhR-mediated transcriptional induction of CYP1A1 can sensitize breast cancer cells to AF. The objective of this study was to investigate the combined antitumor effect of AF and the histone deacetylase inhibitor vorinostat for treating mesenchymal-like triple-negative breast cancer (TNBC) as well as the underlying mechanisms of such treatment. METHODSIn vitro antiproliferative activity of AFP464 (AF prodrug) in breast cancer cell lines was evaluated by MTS assay. In vitro, the combined effect of AFP464 and vorinostat on cell proliferation was assessed by the Chou-Talalay method. In vivo, antitumor activity of AFP464, given alone and in combination with vorinostat, was studied using TNBC xenograft models. Knockdown of ERα was performed using specific, small-interfering RNA. Western blot, quantitative RT-PCR, immunofluorescence, and immunohistochemical staining were performed to study the mechanisms underlying the combined antitumor effect. RESULTSLuminal and basal A subtype breast cancer cell lines were sensitive to AFP464, whereas basal B subtype or mesenchymal-like TNBC cells were resistant. Vorinostat sensitized mesenchymal-like TNBC MDA-MB-231 and Hs578T cells to AFP464. It also potentiated the antitumor activity of AFP464 in a xenograft model using MDA-MB-231 cells. In vitro and in vivo mechanistic studies suggested that vorinostat reactivated ERα expression and restored AhR-mediated transcriptional induction of CYP1A1. CONCLUSIONThe response of breast cancer cells to AF or AFP464 was associated with their gene expression profile. Vorinostat sensitized mesenchymal-like TNBC to AF, at least in part, by reactivating ERα expression and restoring the responsiveness of AhR to AF.
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titleReactivation of estrogen receptor α by vorinostat sensitizes mesenchymal-like triple-negative breast cancer to aminoflavone, a ligand of the aryl hydrocarbon receptor.
descriptionOBJECTIVEAminoflavone (AF) acts as a ligand of the aryl hydrocarbon receptor (AhR). Expression of estrogen receptor α (ERα) and AhR-mediated transcriptional induction of CYP1A1 can sensitize breast cancer cells to AF. The objective of this study was to investigate the combined antitumor effect of AF and the histone deacetylase inhibitor vorinostat for treating mesenchymal-like triple-negative breast cancer (TNBC) as well as the underlying mechanisms of such treatment. METHODSIn vitro antiproliferative activity of AFP464 (AF prodrug) in breast cancer cell lines was evaluated by MTS assay. In vitro, the combined effect of AFP464 and vorinostat on cell proliferation was assessed by the Chou-Talalay method. In vivo, antitumor activity of AFP464, given alone and in combination with vorinostat, was studied using TNBC xenograft models. Knockdown of ERα was performed using specific, small-interfering RNA. Western blot, quantitative RT-PCR, immunofluorescence, and immunohistochemical staining were performed to study the mechanisms underlying the combined antitumor effect. RESULTSLuminal and basal A subtype breast cancer cell lines were sensitive to AFP464, whereas basal B subtype or mesenchymal-like TNBC cells were resistant. Vorinostat sensitized mesenchymal-like TNBC MDA-MB-231 and Hs578T cells to AFP464. It also potentiated the antitumor activity of AFP464 in a xenograft model using MDA-MB-231 cells. In vitro and in vivo mechanistic studies suggested that vorinostat reactivated ERα expression and restored AhR-mediated transcriptional induction of CYP1A1. CONCLUSIONThe response of breast cancer cells to AF or AFP464 was associated with their gene expression profile. Vorinostat sensitized mesenchymal-like TNBC to AF, at least in part, by reactivating ERα expression and restoring the responsiveness of AhR to AF.
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10Gene Expression Regulation, Neoplastic–Drug Effects
11Humans–Drug Therapy
12Hydroxamic Acids–Genetics
13Ligands–Metabolism
14Mesoderm–Pathology
15Mice–Pathology
16Mice, Inbred Balb C–Pathology
17Receptors, Aryl Hydrocarbon–Pathology
18Transcription, Genetic–Pathology
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20Vorinostat–Pathology
21Xenograft Model Antitumor Assays–Pathology
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titleReactivation of estrogen receptor α by vorinostat sensitizes mesenchymal-like triple-negative breast cancer to aminoflavone, a ligand of the aryl hydrocarbon receptor.
authorStark, Karri ; Burger, Angelika ; Wu, Jianmei ; Shelton, Phillip ; Polin, Lisa ; Li, Jing
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abstractOBJECTIVEAminoflavone (AF) acts as a ligand of the aryl hydrocarbon receptor (AhR). Expression of estrogen receptor α (ERα) and AhR-mediated transcriptional induction of CYP1A1 can sensitize breast cancer cells to AF. The objective of this study was to investigate the combined antitumor effect of AF and the histone deacetylase inhibitor vorinostat for treating mesenchymal-like triple-negative breast cancer (TNBC) as well as the underlying mechanisms of such treatment. METHODSIn vitro antiproliferative activity of AFP464 (AF prodrug) in breast cancer cell lines was evaluated by MTS assay. In vitro, the combined effect of AFP464 and vorinostat on cell proliferation was assessed by the Chou-Talalay method. In vivo, antitumor activity of AFP464, given alone and in combination with vorinostat, was studied using TNBC xenograft models. Knockdown of ERα was performed using specific, small-interfering RNA. Western blot, quantitative RT-PCR, immunofluorescence, and immunohistochemical staining were performed to study the mechanisms underlying the combined antitumor effect. RESULTSLuminal and basal A subtype breast cancer cell lines were sensitive to AFP464, whereas basal B subtype or mesenchymal-like TNBC cells were resistant. Vorinostat sensitized mesenchymal-like TNBC MDA-MB-231 and Hs578T cells to AFP464. It also potentiated the antitumor activity of AFP464 in a xenograft model using MDA-MB-231 cells. In vitro and in vivo mechanistic studies suggested that vorinostat reactivated ERα expression and restored AhR-mediated transcriptional induction of CYP1A1. CONCLUSIONThe response of breast cancer cells to AF or AFP464 was associated with their gene expression profile. Vorinostat sensitized mesenchymal-like TNBC to AF, at least in part, by reactivating ERα expression and restoring the responsiveness of AhR to AF.
doi10.1371/journal.pone.0074525
urlhttp://search.proquest.com/docview/1435850004/
date2013-01-01