Stress hormone-mediated acceleration of breast cancer metastasis is halted by inhibition of nitric oxide synthase
Stress hormone-mediated acceleration of breast cancer metastasis is halted by inhibition of nitric oxide synthase
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DOI：
10.1016/j.canlet.2019.05.027
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发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
Flint, Melanie S.
中科院分区：
文献类型：
--
作者：
Flaherty, Renee L.;Intabli, Haya;Flint, Melanie S.
应激激素已被证明是促进恶性肿瘤生长和降低乳腺癌治疗效果的重要介质。糖皮质激素可以通过诱导型一氧化氮合酶（iNOS）介导的途径诱导DNA损伤，从而增加一氧化氮（NO）水平。通过免疫小鼠乳腺癌模型和66CL4乳腺癌细胞，我们发现NOS抑制在减少应激诱导的乳腺癌转移中的新作用。在机制水平上，我们表明糖皮质激素皮质醇诱导与血管生成以及促肿瘤免疫调节相关的关键基因的表达。转录组学分析证实，在荷瘤小鼠的肺中，应激显著富集了与肿瘤发生相关的通路，其中一些通路可以通过NOS抑制来调节。这些结果证明了NOS在应激激素信号传导中的有害参与，以及在高度应激患者中抑制NOS的潜在未来益处。
Stress hormones have been shown to be important mediators in driving malignant growth and reducing treatment efficacy in breast cancer. Glucocorticoids can induce DNA damage through an inducible nitric oxide synthase (iNOS) mediated pathway to increase levels of nitric oxide (NO). Using an immune competent mouse breast cancer model and 66CL4 breast cancer cells we identified a novel role of NOS inhibition to reduce stress-induced breast cancer metastasis. On a mechanistic level we show that the glucocorticoid cortisol induces expression of keys genes associated with angiogenesis, as well as pro-tumourigenic immunomodulation. Transcriptomics analysis confirmed that in the lungs of tumour-bearing mice, stress significantly enriched pathways associated with tumourigenesis, some of which could be regulated with NOS inhibition. These results demonstrate the detrimental involvement of NOS in stress hormone signalling, and the potential future benefits of NOS inhibition in highly stressed patients.