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

Abstract

PurposeChronic stress and related hormones are key in cancer progression. Peroxisome proliferator-activated receptor γ (PPARγ) and its agonists was reported that inducing anti-tumor effect. However, the function of PPARγ in pro-tumorigenic effects induced by chronic stress in breast cancer remains unknown. Herein, we have characterized a novel role of PPARγ and vascular endothelial growth factor (VEGF)/fibroblast growth factor 2 (FGF2) signals in breast cancer promoted by chronic stress.Materials and MethodsWe performed experiments <i>in vivo</i> and <i>in vitro</i> and used bioinformatics data to evaluate the therapeutic potential of PPARγ in breast cancer promoted by stress.ResultsChronic stress significantly inhibited the PPARγ expression and promoted breast cancer <i>in vivo</i>. VEGF/FGF2-mediated angiogenesis increased in the chronic stress group compared to the control group. PPARγ agonist pioglitazone (PioG) injection offset the pro-tumorigenic effect of chronic stress. Moreover, specific β₂-adrenergic receptor (β₂R) antagonist ICI11-8551 inhibited the effect of chronic stress. <i>In vitro</i>, norepinephrine (NE) treatment had a similar tendency to chronic stress. The effect of NE was mediated by the β₂R/adenylate cyclase signaling pathway and suppressed by PioG. PPARγ suppressed VEGF/FGF2 through reactive oxygen species inhibition. Bioinformatics data confirmed that therewas a lowPPARγ expression in breast invasive carcinoma. Lower PPARγ was associated with a significantly worse survival.Conclusion β₂R activation induced by chronic stress and related hormones promotes growth and VEGF/FGF2-mediated angiogenesis of breast cancer by down-regulating PPARγ. Our findings hint that β receptor and PPARγ as two target molecules and the novel role for their agonists or antagonists as clinical medicine in breast cancer therapy