Department of Immunology, School of Medicine, Nankai University, Tianjin, China.
Department of Pediatrics, Tianjin Nankai Hospital, Tianjin, China.
Cancer Res Treat. 2020 Jul;52(3):830-847. doi: 10.4143/crt.2019.510. Epub 2020 Mar 4.
Chronic 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.
We performed experiments in vivo and in vitro and used bioinformatics data to evaluate the therapeutic potential of PPARγ in breast cancer promoted by stress.
Chronic stress significantly inhibited the PPARγ expression and promoted breast cancer in vivo. 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. In vitro, 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.
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.
慢性应激和相关激素是癌症进展的关键。过氧化物酶体增殖物激活受体 γ（PPARγ）及其激动剂被报道具有诱导抗肿瘤作用。然而，PPARγ在慢性应激诱导的乳腺癌促肿瘤形成效应中的功能尚不清楚。在此，我们描述了 PPARγ和血管内皮生长因子（VEGF）/成纤维细胞生长因子 2（FGF2）信号在慢性应激促进的乳腺癌中的新作用。
我们进行了体内和体外实验，并使用生物信息学数据来评估 PPARγ在应激促进的乳腺癌中的治疗潜力。
慢性应激显著抑制 PPARγ表达并促进体内乳腺癌发生。与对照组相比，慢性应激组中 VEGF/FGF2 介导的血管生成增加。PPARγ激动剂吡格列酮（PioG）注射抵消了慢性应激的促肿瘤作用。此外，特异性β2-肾上腺素能受体（β2R）拮抗剂 ICI11-8551 抑制了慢性应激的作用。在体外，去甲肾上腺素（NE）处理也有类似的慢性应激趋势。NE 的作用是通过β2R/腺苷酸环化酶信号通路介导的，并被 PioG 抑制。PPARγ 通过抑制活性氧抑制 VEGF/FGF2。生物信息学数据证实，乳腺癌浸润性癌中 PPARγ 表达较低。较低的 PPARγ与显著较差的生存相关。
慢性应激和相关激素激活的β2R 通过下调 PPARγ 促进乳腺癌的生长和 VEGF/FGF2 介导的血管生成。我们的研究结果表明，β 受体和 PPARγ 作为两个靶分子及其激动剂或拮抗剂作为乳腺癌治疗的新临床应用具有重要意义。
