The PPARgamma antagonist T0070907 suppresses breast cancer cell proliferation and motility via both PPARgamma-dependent and -independent mechanisms.

BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPARγ) is overexpressed in many types of cancer, including breast cancer, and it is regulated by ligand binding and post-translational modifications. It was previously demonstrated that endogenous transactivation promotes an aggressive phenotype of malignant breast cells. This study examines whether selective antagonism of PPARγ with T0070907 is a potential strategy for breast cancer therapy. MATERIALS AND METHODS: PPARγ activation was inhibited using both pharmacological and molecular approaches and proliferation, apoptosis, migration and invasion were measured in MDA-MB-231 and MCF-7 breast cancer cells. RESULTS: T0070907 treatment inhibited proliferation, invasion and migration but did not significantly affect apoptosis. Molecular inhibition using a dominant negative (Δ462) receptor yielded similar results. T007 also mediated a dose-dependent decrease in phosphorylation of PPARγ, and its ability to bind to DNA, and may directly affect mitogen-activated protein kinase signaling. CONCLUSION: These data indicate that inhibiting endogenous PPARγ signaling may be a promising new approach to breast cancer therapy.

Down-regulation of PPARgamma1 suppresses cell growth and induces apoptosis in MCF-7 breast cancer cells.

BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear hormone receptor superfamily and is highly expressed in many human tumors including breast cancer. PPARgamma has been identified as a potential target for breast cancer therapy based on the fact that its activation by synthetic ligands affects the differentiation, proliferation, and apoptosis of cancer cells. However, the controversial nature of current studies and disappointing results from clinical trials raise questions about the contribution of PPARgamma signaling in breast cancer development in the absence of stimulation by exogenous ligands. Recent reports from both in vitro and in vivo studies are inconsistent and suggest that endogenous activation of PPARgamma plays a much more complex role in initiation and progression of cancer than previously thought. RESULTS: We have previously demonstrated that an increase in expression of PPARgamma1 in MCF-7 breast cancer cells is driven by a tumor-specific promoter. Myc-associated zinc finger protein (MAZ) was identified as a transcriptional mediator of PPARgamma1 expression in these cells. In this study, using RNA interference (RNAi) to inhibit PPARgamma1 expression directly or via down-regulation of MAZ, we report for the first time that a decrease in PPARgamma1 expression results in reduced cellular proliferation in MCF-7 breast cancer cells. Furthermore, we demonstrate that these changes in proliferation are associated with a significant decrease in cell transition from G1 to the S phase. Using a dominant-negative mutant of PPARgamma1, Delta462, we confirmed that PPARgamma1 acts as a pro-survival factor and showed that this phenomenon is not limited to MCF-7 cells. Finally, we demonstrate that down-regulation of PPARgamma1 expression leads to an induction of apoptosis in MCF-7 cells, confirmed by analyzing Bcl-2 expression and PARP-1 cleavage. CONCLUSION: Thus, these findings suggest that an increase in PPARgamma1 signaling observed in breast cancer contributes to an imbalance between proliferation and apoptosis, and may be an important hallmark of breast tumorigenesis. The results presented here also warrant further investigation regarding the use of PPARgamma ligands in patients who are predisposed or already diagnosed with breast cancer.