Targeting peroxisome proliferator-activated receptor g to increase estrogen-induced apoptosis in estrogen-deprived breast cancer cells

Peroxisome proliferator-activated receptor g (PPARg) is an important transcription factor that modulates lipid metabolism and inflammation. However, it remains unclear whether PPARg is involved in modulation of estrogen (E₂)-induced inflammation, thus affecting apoptosis of E₂-deprived breast cancer cells, MCF-7:5C and MCF-7:2A. Here, we demonstrated that E₂ treatment suppressed the function of PPARg in both cell lines, although the suppressive effect in MCF-7:2A cells was delayed owing to high PPARg expression. Activation of PPARg by a specific agonist, pioglitazone, selectively blocked the induction of TNFa expression by E₂, but did not affect other adipose inflammatory genes, such as fatty acid desaturase 1 and IL6. This suppression of TNFa expression by pioglitazone was mainly mediated by transrepression of nuclear factor-kB (NF-kB) DNA-binding activity. A novel finding was that NF-kB functions as an oxidative stress inducer in MCF-7:5C cells but an antioxidant in MCF-7:2A cells. Therefore, the NF-kB inhibitor JSH-23 displayed effects equivalent to those of pioglitazone, with complete inhibition of apoptosis in MCF-7:5C cells, but it increased E₂-induced apoptosis in MCF-7:2A cells. Depletion of PPARg by siRNA or the PPARg antagonist T0070907 accelerated E₂-induced apoptosis, with activation of NF-kB–dependent TNFa and oxidative stress. For the first time, we demonstrated that PPARg is a growth signal and has potential to modulate NF-kB activity and oxidative stress in E₂-deprived breast cancer cell lines. All of these findings suggest that anti-PPARg therapy is a novel strategy to improve the therapeutic effects of E₂-induced apoptosis in E₂-deprived breast cancer.