Signal cross-talk between estrogen receptor alpha and beta and the peroxisome proliferator-activated receptor gamma1 in MDA-MB-231 and MCF-7 breast cancer cells

We have previously demonstrated that peroxisome proliferator-activated receptor gamma (PPARγ) is expressed and transcriptionally responsive to both synthetic and natural ligands in a variety of human breast cancer cells. We also observed significant differences in basal and ligand-mediated transactivation of PPARγ in cells with variable expression of the estrogen receptor. While previous reports indicate that PPARγ can mediate the expression of estrogen target genes, no data have suggested that estrogen receptor (ER) expression can alter the transcriptional regulation of PPARγ target gene expression. Here we have demonstrated that the expression of either ERα or β, but not the androgen or aryl hydrocarbon receptors, lowers both basal and stimulated PPARγ-mediated reporter activity. Interestingly, the presence of an ER antagonist does not inhibit this response while estradiol treatment further inhibits the ligand-stimulated transactivation of PPARγ in cells expressing ERα but not ERβ. Cells transfected with ERα deletion mutants demonstrate that the DNA binding domain of the ER is required to repress PPAR transactivation in these cells. Finally, using RNase protection assays we show that the inhibition of PPAR function is not due to a decrease in the expression of PPARγ. These data suggest that signal cross talk exists bidirectionally between PPARγ and ER in breast cancer cells.