期刊
MOLECULAR NUTRITION & FOOD RESEARCH
卷 57, 期 5, 页码 840-853出版社
WILEY-BLACKWELL
DOI: 10.1002/mnfr.201200560
关键词
Estrogen receptor; Hsp90; p38MAPK; Progesterone receptor
资金
- PRIN-MIUR
- NIH/NCI [R01 CA72038]
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- 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- gene promoter show that EGCG downregulates ER- protein, mRNA, and gene promoter activity with a concomitant reduction of ER- genomic and nongenomic signal. These events occur through p38MAPK/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- 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- 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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