Activation of β2-Adrenergic Receptor Promotes Growth and Angiogenesis in Breast Cancer by Down-regulating PPARγ

Purpose Chronic stress and related hormones are key in cancer progression. Peroxisome proliferator-activated receptor gamma (PPAR gamma) and its agonists was reported that inducing anti-tumor effect. However, the function of PPAR gamma in pro-tumorigenic effects induced by chronic stress in breast cancer remains unknown. Herein, we have characterized a novel role of PPAR gamma 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 PPAR gamma in breast cancer promoted by stress. Results Chronic stress significantly inhibited the PPAR gamma expression and promoted breast cancer in vivo. VEGF/FGF2-mediated angiogenesis increased in the chronic stress group compared to the control group. PPAR gamma agonist pioglitazone (PioG) injection offset the pro-tumorigenic effect of chronic stress. Moreover, specific beta(2)-adrenergic receptor (beta R-2) 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 beta R-2/adenylate cyclase signaling pathway and suppressed by PioG. PPAR gamma suppressed VEGF/FGF2 through reactive oxygen species inhibition. Bioinformatics data confirmed that there was a low PPAR gamma expression in breast invasive carcinoma. Lower PPAR gamma was associated with a significantly worse survival. Conclusion beta R-2 activation induced by chronic stress and related hormones promotes growth and VEGF/ FGF2-mediated angiogenesis of breast cancer by down-regulating PPAR gamma. Our findings hint that beta receptor and PPAR gamma as two target molecules and the novel role for their agonists or antagonists as clinical medicine in breast cancer therapy.