Document Detail


Molecular Mechanism of Action of Bisphenol and Bisphenol-A Mediated by Estrogen Receptor alpha in Growth and Apoptosis of Breast Cancer Cells.
MedLine Citation:
PMID:  23373633     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
BACKGROUND AND PURPOSE: Estrogen receptor alpha (ERα) binds to different ligand which can function as complete / partial estrogen-agonist or antagonist. This depends on the chemical structure of the ligands which modulates the transcriptional activity of the estrogen-responsive genes by altering the conformation of the liganded-ERα complex. This study determined the molecular mechanism of estrogen-agonistic / antagonistic action of structurally similar ligands, bisphenol (BP) and bisphenol-A (BPA) on cell proliferation and apoptosis of ERα+ve breast cancer cells. EXPERIMENTAL APPROACH: DNA was measured to assess the proliferation and apoptosis of breast cancer cells. RT- PCR and ChIP assays were performed to quantify the transcripts of TFF1 gene and recruitment of ERα and SRC3 at the promoter of TFF1 gene, respectively. Molecular docking was used to delineate the binding modes of BP and BPA with the ERα. PCR-based arrays were used study the regulation of the apoptotic genes. KEY RESULTS: BP and BPA induced the proliferation of breast cancer cells, however, unlike BPA, BP failed to induce apoptosis. BPA consistently acted as an agonist in our studies but BP exhibited mixed agonistic/antagonistic properties. Molecular docking revealed agonistic and antagonistic mode of binding for BPA and BP respectively. BPA treatment resembled E2 treatment in terms of PCR-based regulation of apoptotic genes whereas BP was similar to 4OHT treatment. CONCLUSIONS AND IMPLICATIONS: The chemical structure of ERα ligand determines the agonistic or antagonistic biological responses by the virtue of their binding mode, conformation of the liganded-ERα complex and the context of the cellular function. ABBREVIATIONS: 4OHT, 4-hydroxy tamoxifen; BP, bisphenol; BPA, bisphenol-A; ChIP, chromatin-immuno precipitation assay; DES, di-ethyl stilbestrol; E2, 17β-estradiol; ERα, estrogen receptor alpha; LBD, ligand binding domain; RAL, raloxifene; RT-PCR, real time polymerase chain reaction; SRC3, steroid co-activator 3; TFF1, trefoil factor 1;
Authors:
S Sengupta; I Obiorah; P Y Maximov; R Curpan; V C Jordan
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-2-4
Journal Detail:
Title:  British journal of pharmacology     Volume:  -     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-2-4     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society.
Affiliation:
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC.
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