Abstract
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. 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. 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.
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