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 (PPARgamma) 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 PPARgamma in cells with variable expression of the estrogen receptor. While previous reports indicate that PPARgamma can mediate the expression of estrogen target genes, no data have suggested that estrogen receptor (ER) expression can alter the transcriptional regulation of PPARgamma target gene expression. Here we have demonstrated that the expression of either ERalpha or beta, but not the androgen or aryl hydrocarbon receptors, lowers both basal and stimulated PPARgamma-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 PPARgamma in cells expressing ERalpha but not ERbeta. Cells transfected with ERalpha 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 PPARgamma. These data suggest that signal cross talk exists bidirectionally between PPARgamma and ER in breast cancer cells.
Wang
Xin
X
Department of Molecular and Biomedical Pharmacology, University of Kentucky School of Medicine, Lexington, KY 40536-0298, USA.
Kilgore
Michael W
MW
D001665:Binding Sites / Q000502:physiology; D001943:Breast Neoplasms / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000502:physiology; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D005260:Female; D006801:Humans; D020239:Receptor Cross-Talk; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology; D011960:Receptors, Estrogen / Q000502:physiology*; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D014157:Transcription Factors