Activation of β2-Adrenergic Receptor Promotes Growth and Angiogenesis in Breast Cancer by Down-regulating PPARγ.
2020
Purpose: Chronic stress and related hormones are key in cancer progression. Peroxisome proliferator-activated receptor gamma (PPARgamma) and its agonists was reported that inducing anti-tumor effect. However, the function of PPARgamma in pro-tumorigenic effects induced by chronic stress in breast cancer remains unknown. Herein, we have characterized a novel role of PPARgamma and vascular endothelial growth factor (VEGF)/fibroblast growth factor 2 (FGF2) signals in breast cancer promoted by chronic stress. Materials and Methods: We performed experiments in vivo and in vitro and used bioinformatics data to evaluate the therapeutic potential of PPARgamma in breast cancer promoted by stress. Results: Chronic stress significantly inhibited the PPARgamma expression and promoted breast cancer in vivo. VEGF/FGF2-mediated angiogenesis increased in the chronic stress group compared to the control group. PPARgamma agonist pioglitazone (PioG) injection offset the pro-tumorigenic effect of chronic stress. Moreover, specific beta2-adrenergic receptor (beta2R) antagonist ICI118551 inhibited the effect of chronic stress. In vitro, Norepinephrine (NE) treatment had a similar tendency to chronic stress. The effect of NE was mediated by the beta2R/adenylate cyclase signaling pathway and suppressed by PioG. PPARgamma suppressed VEGF/ FGF2 through ROS inhibition. Bioinformatics data confirmed that there was a low PPARgamma expression in breast invasive carcinoma. Lower PPARgamma was associated with a significantly worse survival. Conclusion: beta2-adrenergic receptor activation induced by chronic stress and related hormones promotes growth and VEGF/FGF2-mediated angiogenesis of breast cancer by down-regulating PPARgamma. Our findings hint that beta receptor and PPARgamma as two target molecules and the novel role for their agonists or antagonists as clinical medicine in breast cancer therapy.
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