Estrogen receptor α binds to peroxisome proliferator-activated receptor response element and negatively interferes with peroxisome proliferator-activated receptor γ signaling in breast cancer cells

Purpose: The molecular mechanisms involved in the repressive effects exerted by estrogen receptors (ER) on peroxisome proliferator- activated receptor (PPAR) gamma- mediated transcriptional activity remain to be elucidated. The aim of the present study was to provide new insight into the crosstalk between ER alpha and PPAR gamma pathways in breast cancer cells. Experimental Design: Using MCF7 and HeLa cells as model systems, we did transient transfections and electrophoretic mobility shift assay and chromatin immunoprecipitation studies to evaluate the ability of ERa. to influence PPAR response element - mediated transcription. A possible direct interaction between ERa and PPAR gamma was ascertained by coimmunoprecipitation assay, whereas their modulatory role in the phosphaticlylinositol 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 in hormone-dependent MCF7 breast cancer cells. Results: Our data show for the first time that ER alpha binds to PPAR response element and represses its transactivation. Moreover, we have documented the physical and functional interactions of ERa and PPAR-gamma, which also involve the p85 regulatory subunit of PI3K. Interestingly, ER alpha and PPAR-gamma 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 ligands 17 beta-estradiol and BR L49653 on MCF7 cell proliferation. Conclusion: ER alpha physically associates with PPAR-gamma and functionally interferes with PPAR-gamma signaling. This crosstalk could be taken into account in setting new pharmacologic strategies for breast cancer disease.