THE MECHANISM OF PPARN3-MEDIATED DOWN-REGULATION OF SODIUM HYDROGEN EXCHANGER 1 (NHE1) GENE EPXRESSION AND ITS INHIBITION BY ESTROGEN RECEPTOR N1

Abstract

Peroxisome proliferator-activated receptor gamma (PPARgamma) has been associated with the process of carcinogenesis, which therefore presents a promising target for cancer treatment. We recently showed that exposure of breast cancer cells to PPARgamma ligands repressed NHE1 expression and inhibition of NHE1 expression in breast cancer cells increased their sensitivity to doxorubicin and paclitaxel. However, recent evidence of cross talks between PPARgamma and the estrogen receptor (ER) has been demonstrated. We show that E2 prevented the inhibition of NHE1 expression by PPARgamma and the results suggest that activated ERalpha physically associate with PPARgamma and functionally interfered with PPARgamma binding efficiency to NHE1 promoter. Disruption of ERalpha-PPARgamma complex by anti-estrogens led to increased efficacy of the anti-tumor activity of PPARgamma and its repressive effect on NHE1 gene expression in vivo, which could be a potential combination therapy for enhanced efficacy of anti-estrogen therapy in breast cancer patients.