title: In vitro mechanism for downregulation of ER-α expression by epigallocatechin gallate in ER+/PR+ human breast cancer cells.
abstract: METHODS
  Exposure of the breast to estrogens and other sex hormones is an important cancer risk factor and estrogen receptor downregulators are attracting significant clinical interest. Epigallocatechin gallate (EGCG), a polyphenolic compound found in green tea, has gained considerable attention for its antitumor properties. Here we aimed to investigate the molecular mechanisms through which EGCG regulates ER-α expression in ER+ PR+ breast cancer cells.
  
  
  METHODS
  Western blotting analysis, real-time PCR, and transient transfections of deletion fragments of the ER-α gene promoter show that EGCG downregulates ER-α protein, mRNA, and gene promoter activity with a concomitant reduction of ER-α genomic and nongenomic signal. These events occur through p38(MAPK) /CK2 activation, causing the release from Hsp90 of progesterone receptor B (PR-B) and its consequent nuclear translocation as evidenced by immunofluorescence studies. EMSA, and ChIP assay reveal that, upon EGCG treatment, PR-B is recruited at the half-PRE site on ER-α promoter. This is concomitant with the formation of a corepressor complex containing NCoR and HDAC1 while RNA polymerase II is displaced. The events are crucially mediated by PR-B isoform, since they are abrogated with PR-B siRNA.
  
  
  CONCLUSIONS
  Our data provide evidence for a mechanism by which EGCG downregulates ER-α and explains the inhibitory action of EGCG on the proliferation of ER+ PR+ cancer cells tested. We suggest that the EGCG/PR-B signaling should be further exploited for clinical approach.
authors: Centro Sanitario, University of Calabria, Arcavacata di Rende (CS), Italy.
authors: Francesca
authors: F
authors: De Amicis
authors: Alessandra
authors: A
authors: Russo
authors: Paola
authors: P
authors: Avena
authors: Marta
authors: M
authors: Santoro
authors: Adele
authors: A
authors: Vivacqua
authors: Daniela
authors: D
authors: Bonofiglio
authors: Loredana
authors: L
authors: Mauro
authors: Saveria
authors: S
authors: Aquila
authors: Donatella
authors: D
authors: Tramontano
authors: Suzanne A W
authors: SA
authors: Fuqua
authors: Sebastiano
authors: S
authors: Andò
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D015536:Down-Regulation; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D056971:Nuclear Receptor Co-Repressor 1 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D013662:Tea / Q000737:chemistry
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D018841:HSP90 Heat-Shock Proteins; C539127:NCOR1 protein, human; D056971:Nuclear Receptor Co-Repressor 1; D013662:Tea; D002392:Catechin; C045651:epigallocatechin gallate; D012319:RNA Polymerase II; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1