Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702.
Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway, Galway H91 TK33, Ireland.
Proc Natl Acad Sci U S A. 2017 Dec 5;114(49):13030-13035. doi: 10.1073/pnas.1709119114. Epub 2017 Oct 27.
Proinflammatory signaling pathways are commonly up-regulated in breast cancer. In estrogen receptor-negative (ER) and triple-negative breast cancer (TNBC), nitric oxide synthase-2 (NOS2) and cyclooxygenase-2 (COX2) have been described as independent predictors of disease outcome. We further explore these findings by investigating the impact of their coexpression on breast cancer survival. Elevated coexpression of NOS2/COX2 proteins is a strong predictor of poor survival among ER patients (hazard ratio: 21). Furthermore, we found that the key products of NOS2 and COX2, NO and prostaglandin E2 (PGE2), respectively, promote feed-forward NOS2/COX2 crosstalk in both MDA-MB-468 (basal-like) and MDA-MB-231 (mesenchymal-like) TNBC cell lines in which NO induced COX2 and PGE2 induced NOS2 proteins. COX2 induction by NO involved TRAF2 activation that occurred in a TNFα-dependent manner in MDA-MB-468 cells. In contrast, NO-mediated TRAF2 activation in the more aggressive MDA-MB-231 cells was TNFα independent but involved the endoplasmic reticulum stress response. Inhibition of NOS2 and COX2 using amino-guanidine and aspirin/indomethacin yielded an additive reduction in the growth of MDA-MB-231 tumor xenografts. These findings support a role of NOS2/COX2 crosstalk during disease progression of aggressive cancer phenotypes and offer insight into therapeutic applications for better survival of patients with ER and TNBC disease.
促炎信号通路在乳腺癌中常被上调。在雌激素受体阴性（ER）和三阴性乳腺癌（TNBC）中，已描述一氧化氮合酶-2（NOS2）和环氧化酶-2（COX2）是疾病结局的独立预测因子。我们通过研究它们的共表达对乳腺癌生存的影响进一步探讨了这些发现。NOS2/COX2 蛋白的高共表达是 ER 患者生存不良的强烈预测因子（风险比：21）。此外，我们发现 NOS2 和 COX2 的关键产物，分别为一氧化氮（NO）和前列腺素 E2（PGE2），在 MDA-MB-468（基底样）和 MDA-MB-231（间质样）TNBC 细胞系中分别促进 NOS2/COX2 串扰，其中 NO 诱导 COX2，PGE2 诱导 NOS2 蛋白。NO 诱导的 COX2 涉及 TRAF2 的激活，该激活在 MDA-MB-468 细胞中以 TNFα 依赖性方式发生。相比之下，NO 介导的在更具侵袭性的 MDA-MB-231 细胞中 TRAF2 激活与 TNFα 无关，但涉及内质网应激反应。使用氨基胍和阿司匹林/吲哚美辛抑制 NOS2 和 COX2 可使 MDA-MB-231 肿瘤异种移植的生长减少，具有相加作用。这些发现支持 NOS2/COX2 串扰在侵袭性癌症表型疾病进展中的作用，并为改善 ER 和 TNBC 疾病患者的生存提供了治疗应用的见解。
