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Estrogen Receptor Binds to Peroxisome Proliferator–Activated Receptor Response Element and Negatively Interferes with Peroxisome Proliferator–Activated Receptor Signaling in Breast Cancer Cells

Authors' Affiliations: Departments of ¹ Pharmaco-Biology and ² Cell Biology, and ³ Centro Sanitario, University of Calabria, Cosenza, Italy

Requests for reprints: Sebastiano Andò, Department of Cell Biology, University of Calabria, Cosenza 87036, Italy. Phone: 39-0984-496201; Fax: 39-0984-496203; E-mail: sebastiano.ando{at}unical.it.

Purpose: The molecular mechanisms involved in the repressive effects exerted by estrogen receptors (ER) on peroxisome proliferator–activated receptor (PPAR) –mediated transcriptional activity remain to be elucidated. The aim of the present study was to provide new insight into the crosstalk between ER and PPAR 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 ER to influence PPAR response element–mediated transcription. A possible direct interaction between ER and PPAR was ascertained by coimmunoprecipitation assay, 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 in hormone-dependent MCF7 breast cancer cells.

Results: Our data show for the first time that ER binds to PPAR response element and represses its transactivation. Moreover, we have documented the physical and functional interactions of ER and PPAR, which also involve the p85 regulatory subunit of PI3K. Interestingly, ER and PPAR 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 17ß-estradiol and BRL49653on MCF7 cell proliferation.

Conclusion: ER physically associates with PPAR and functionally interferes with PPAR signaling. This crosstalk could be taken into account in setting new pharmacologic strategies for breast cancer disease.

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