Targeting the peroxisome proliferator-activated receptor gamma one in the treatment of breast cancer.

Abstract

Abstract Abstract #3055 Peroxisome proliferator-activated receptor gamma 1 (PPARγ1) is a member of the nuclear hormone receptor superfamily and is over expressed in breast cancer compared to human mammary epithelial cells (HMEC). Although synthetic ligands of PPARγ have been reported to mediate differentiation, inhibit proliferation, and induce apoptosis of cancer cells in culture it remains unclear whether these are mediated through PPARγ or by off target effects. Furthermore, the controversial nature of these studies and the disappointing results from clinical trials raise questions about the efficacy of these drugs in treating breast cancer. Recent work from our lab and others suggests that targeting the expression or endogenous transactivation of PPARγ represents a novel strategy in the treatment of breast cancer. We have previously demonstrated that the increase in PPARγ1 expression in seen in breast cancer cells is driven by a tumor-specific promoter. Furthermore, we have identified the myc-associated zinc finger protein (MAZ) as a critical mediator of PPARγ1 expression in these cells. In this study, we further demonstrated the significance of MAZ in the transcriptional regulation of PPARγ1 and confirmed that high expression of PPARγ1 in MCF-7 breast cancer cells is MAZ dependent. Additionally, using RNA interference (RNAi) techniques to knockdown PPARγ1 or MAZ or driving the expression of a dominant negative form of PPARγ1 in MCF-7 breast cancer cells, we demonstrated that blocking the expression of either protein resulted in reduced cellular proliferation and enhanced apoptosis. These findings suggest that in the absence of any exogenous ligand an increase in PPARγ1 signaling, driven at least in part by MAZ, contributes to an imbalance between proliferation and apoptosis, and may be an important mediator or of breast cancer progression. These results also highlight the need to understand the molecular mechanisms that drives tumor specific expression of PPARγ1 and development pure antagonist as a therapeutic treatment of this devastating disease. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3055.