Growth of triple-negative breast cancer cells relies upon coordinate autocrine expression of the proinflammatory cytokines IL-6 and IL-8.
Growth of triple-negative breast cancer cells relies upon coordinate autocrine expression of the proinflammatory cytokines IL-6 and IL-8.
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DOI：
10.1158/0008-5472.can-12-4524-t
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发表时间：
2013-06-01
期刊：
影响因子：
11.2
通讯作者：
Brown PH
中科院分区：
文献类型：
--
作者：
Hartman ZC;Poage GM;den Hollander P;Tsimelzon A;Hill J;Panupinthu N;Zhang Y;Mazumdar A;Hilsenbeck SG;Mills GB;Brown PH
三阴性乳腺癌（TNBC）是侵袭性的，没有有效的靶向治疗。联合数据库分析确定了32个在TNBC中差异表达的炎症相关基因，其中10个被证明对锚定非依赖性生长至关重要。在TNBC细胞中，LPA-LPAR 2-EZH 2 NF-κ B信号级联对于IL-6、IL-8和CXCL 1的表达是必需的。同时抑制IL-6和IL-8表达显著抑制体外集落形成和细胞存活，并抑制体内肿瘤植入和生长。患者标本的考克斯多变量分析显示，IL-6和IL-8表达预测患者的生存时间。总之，这些发现为双重抑制IL-6/IL-8信号传导作为改善TNBC患者结局的治疗策略提供了理论基础。
Triple-negative breast cancers (TNBCs) are aggressive with no effective targeted therapies. A combined database analysis identified 32 inflammation-related genes differentially expressed in TNBCs, 10 proved critical for anchorage-independent growth. In TNBC cells a LPA-LPAR2-EZH2 NF-kappaB signaling cascade was essential for expression of IL-6, IL-8 and CXCL1. Concurrent inhibition of IL-6 and IL-8 expression dramatically inhibited colony formation and cell survival in vitro and stanched tumor engraftment and growth in vivo. A Cox multivariable analysis of patient specimens revealed that IL-6 and IL-8 expression predicted patient survival times. Together these findings offer a rationale for dual inhibition of IL-6/IL-8 signaling as a therapeutic strategy to improve outcomes for TNBC patients.