In vitro mechanism for downregulation of ER-α expression by epigallocatechin gallate in ER+/PR+ human breast cancer cells.

Abstract

SCOPE:

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.

MATERIAL AND 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.

CONCLUSION:

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: Francesca De Amicis, Alessandra Russo, Paola Avena, Marta Santoro, Adele Vivacqua, Daniela Bonofiglio, Loredana Mauro, Saveria Aquila, Donatella Tramontano, Suzanne A W Fuqua, Sebastiano Andò
• Journal: Molecular nutrition & food research (Mol Nutr Food Res) Vol. 57 Issue 5 Pg. 840-53 (May 2013) ISSN: 1613-4133 [Electronic] Germany
• PMID: 23322423 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• ESR1 protein, human
• Estrogen Receptor alpha
• HSP90 Heat-Shock Proteins
• NCOR1 protein, human
• Nuclear Receptor Co-Repressor 1
• Tea
• Catechin
• epigallocatechin gallate
• RNA Polymerase II
• HDAC1 protein, human
• Histone Deacetylase 1

Topics

• Breast Neoplasms (genetics, pathology)
• Catechin (analogs & derivatives, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chromatin Immunoprecipitation
• Down-Regulation
• Estrogen Receptor alpha (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• HSP90 Heat-Shock Proteins (genetics, metabolism)
• Histone Deacetylase 1 (genetics, metabolism)
• Humans
• Nuclear Receptor Co-Repressor 1 (genetics, metabolism)
• Promoter Regions, Genetic
• RNA Polymerase II (genetics, metabolism)
• Real-Time Polymerase Chain Reaction
• Signal Transduction
• Tea (chemistry)