Crosstalk between the peroxisome proliferator-activated receptor γ (PPARγ) and the vitamin D receptor (VDR) in human breast cancer cells: PPARγ binds to VDR and inhibits 1α,25-dihydroxyvitamin D3 mediated transactivation

Heterodimerization and cross-talk between nuclear hormone receptors often occurs. For example, estrogen receptor alpha (ER alpha) physically binds to peroxisome proliferator-activated receptor gamma (PPAR gamma) and inhibits its transcriptional activity. The interaction between PPAR gamma and the vitamin D receptor (VDR) however, is unknown. Here, we elucidate the molecular mechanisms linking PPAR gamma and VDR signaling, and for the first time we show that PPAR gamma physically associates with VDR in human breast cancer cells. We found that overexpression of PPAR gamma decreased 1 alpha,25-dihydroxyvitamin D-3 (1,25D(3)) mediated transcriptional activity of the vitamin D target gene, CYP24A1, by 49% and the activity of VDRE-luc, a vitamin D responsive reporter, by 75% in T47D human breast cancer cells. Deletion mutation experiments illustrated that helices 1 and 4 of PPAR gamma's hinge and ligand binding domains, respectively, governed this suppressive function. Additionally, abrogation of PPAR gamma's AF2 domain attenuated its repressive action on 1,25D(3) transactivation, indicating that this domain is integral in inhibiting VDR signaling. PPAR gamma was also found to compete with VDR for their binding partner retinoid X receptor alpha (RXR alpha). Overexpression of RXR alpha blocked PPAR gamma's suppressive effect on 1,25D(3) action, enhancing VDR signaling. In conclusion, these observations uncover molecular mechanisms connecting the PPAR gamma and VDR pathways. (C) 2012 Elsevier Inc. All rights reserved.