Purpose: The molecular mechanisms involved in the repressive effects exerted by estrogen receptors (ER) on peroxisome proliferator- activated receptor (PPAR) gamma mediated transcriptionalactivity remain to be elucidated. The aim of the present study was to provide new insight into the crosstalk between ERa and PPARg pathways in breast cancer cells. Experimental Design: Using MCF7 and HeLa cells as model systems, we did transient transfectionsand electrophoretic mobility shift assay and chromatin immunoprecipitation studies toevaluate the ability of ERa to influence PPAR response element mediated transcription. A possibledirect interaction between ERa and PPARg was ascertained by coimmunoprecipitationassay, whereas their modulatory role in the phosphatidylinositol 3-kinase (PI3K)/AKT pathway was evaluated by determining PI3K activity and AKT phosphorylation. As a biological counterpart,we investigated the growth response to the cognate ligands of both receptors inhormone-dependent MCF7 breast cancer cells.Results: Our data showfor the first time that ERa binds to PPAR response element and represses its transactivation. Moreover, we have documented the physical and functional interactions ofERa and PPARg, which also involve the p85 regulatory subunit of PI3K. Interestingly, ERa andPPARg pathways have an opposite effect on the regulation of the PI3K/AKT transduction cascade, explaining, at least in part, the divergent response exerted by the cognate ligands17h-estradiol and BRL49653 on MCF7 cell proliferation.Conclusion: ERa physically associates with PPARg and functionally interferes with PPARg signaling. This crosstalk could be taken into account in setting new pharmacologic strategies forbreast cancer disease.
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|Titolo:||Estrogen receptor alpha binds to peroxisome proliferator-activated receptor response element and negatively interferes with peroxisome proliferator-activated receptor gamma signaling in breast cancer cells|
|Data di pubblicazione:||2005|
|Citazione:||Estrogen receptor alpha binds to peroxisome proliferator-activated receptor response element and negatively interferes with peroxisome proliferator-activated receptor gamma signaling in breast cancer cells / Bonofiglio, Daniela; Gabriele, S.; Aquila, S.; Catalano, S.; Gentile, M.; Middea, E.; Giordano, Francesca; Ando', Sebastiano. - In: CLINICAL CANCER RESEARCH. - ISSN 1078-0432. - 11:17(2005), pp. 6137-6147.|
|Appare nelle tipologie:||1.1 Articolo in rivista|