Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, 200032, China.
Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, 200032, China.
Cancer Lett. 2018 Jan 1;412:69-80. doi: 10.1016/j.canlet.2017.09.030. Epub 2017 Sep 28.
Metastasis and chemoresistance are two major causes of breast cancer death. We show here that the chemokine receptor CXCR2 was overexpressed in breast cancer cell lines and tissues. CXCR2 promoted anti-apoptosis, anti-senescence, and epithelial-to-mesenchymal transition (EMT) of breast cancer cells, leading to the enhanced metastasis and chemoresistance. Further study suggested that AKT1 and cyclooxygenase-2 (COX2; PTGS2) might mediate the CXCR2 signaling to inversely control the breast cancer metastasis and chemoresistance through the regulation of EMT, apoptosis, and senescence. Analyses of clinical data indicate that the high expression of CXCR2 was correlated with the high expression of COX2 and the low expression of AKT1, P85α, E-cadherin, and β-catenin in cancer tissues. Poor outcomes were associated with the high expression of CXCR2 or COX2 while favorable survivals were associated with the high expression of P85α, AKT1, or E-cadherin in all cancer patients. Cox multivariate analysis demonstrated that CXCR2, COX2, and AKT1 could be independent predictors for disease free survivals. All these data suggest that CXCR2 promotes breast cancer metastasis and chemoresistance via suppressing AKT1 and activating COX2. Thus, antagonists of the CXCR2 signaling molecules may be used to treat breast cancer patients particularly with high metastasis and chemoresistance.
转移和化疗耐药是导致乳腺癌死亡的两个主要原因。我们在此表明，趋化因子受体 CXCR2 在乳腺癌细胞系和组织中过表达。CXCR2 促进乳腺癌细胞的抗凋亡、抗衰老和上皮间质转化 (EMT)，从而增强转移和化疗耐药性。进一步的研究表明，AKT1 和环氧化酶-2 (COX2; PTGS2) 可能通过调节 EMT、凋亡和衰老来介导 CXCR2 信号，从而反向控制乳腺癌转移和化疗耐药性。临床数据分析表明，CXCR2 的高表达与 COX2 的高表达以及 AKT1、P85α、E-钙粘蛋白和 β-连环蛋白在癌组织中的低表达相关。高 CXCR2 或 COX2 表达与不良预后相关，而所有癌症患者中 P85α、AKT1 或 E-钙粘蛋白高表达与良好的生存相关。Cox 多因素分析表明，CXCR2、COX2 和 AKT1 可作为无病生存的独立预测因子。所有这些数据表明，CXCR2 通过抑制 AKT1 和激活 COX2 促进乳腺癌转移和化疗耐药性。因此，CXCR2 信号分子的拮抗剂可能用于治疗乳腺癌患者，特别是具有高转移和化疗耐药性的患者。
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