American Association for Cancer Research
15357163mct180088-sup-195995_3_supp_5016388_pdpdrl.pptx (10.09 MB)

Figure S2 from Targeting Peroxisome Proliferator-Activated Receptor γ to Increase Estrogen-Induced Apoptosis in Estrogen-Deprived Breast Cancer Cells

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posted on 2023-04-03, 15:04 authored by Ping Fan, Balkees Abderrahman, Tina S. Chai, Smitha Yerrum, V. Craig Jordan

E2 suppressed the expression of PPARγ target gene ACOX3 in three breast cancer cell lines. MCF-7 cells were transferred from phenol red containing medium to E2-free medium for 3 days. Next, (A) MCF-7, (B) MCF-7:5C, and (C) MCF-7:2A cells were seeded in six-well plates. After 24 hours, cells were treated with a vehicle control (0.1% EtOH) or E2 (1 nM) for 24, 48, 72 hours. Cells were then harvested in TRIzol reagent. ACOX3 expression levels were quantitated using RT-PCR. *P<0.05 compared with control; **P<0.001 compared with control.



Susan G. Komen for the Cure Foundation

Cancer Prevention Research Institute of Texas



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

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