Yin Lina, Gao Yun, Zhang Xuxia, Wang Jing, Ding Defang, Zhang Yaping, Zhang Junxiang, Chen Honghong
Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, Shanghai, China.
Oncotarget. 2016 Jul 5;7(27):42126-42138. doi: 10.18632/oncotarget.9704.
Triple-negative breast cancer (TNBC) is one of the most difficult breast cancers to treat because there is no targeted treatment, and conventional cytotoxic chemotherapy followed by adjuvant radiation therapy is the standard of care for patients with TNBC. We herein reported that ionizing radiation (IR) induced Wnt3a, LRP6 and β-catenin expression and consequently activated Wnt/β-catenin signaling in TNBC MDA-MB-231, MDA-MB-468 and Hs578T cells. Moreover, depletion of β-catenin by shRNA sensitized TNBC cells to IR, whereas treatment of Wnt3a protein or overexpression of β-catenin resulted in radioresistance of TNBC cells. Niclosamide, a potent inhibitor of Wnt/β-catenin signaling, not only inhibited constitutive Wnt/β-catenin signaling, but also blocked IR-induced Wnt/β-catenin signaling in TNBC cells. In addition, niclosamide sensitized TNBC cells to IR, prevented Wnt3a-induced radioresistance, and overcame β-catenin-induced radioresistance in TNBC cells. Importantly, animals treated with the combination of niclosamide and γ-ray local tumor irradiation had significant inhibition of MDA-MB-231 tumor growth compared with treated with local tumor irradiation alone. These findings indicate that Wnt/β-catenin signaling pathway plays an important role in the development of radioresistance of TNBC cells, and that niclosamide had significant radiosensitizing effects by inhibiting Wnt/β-catenin signaling in TNBC cells. Our study also provides rationale for further preclinical and clinical evaluation of niclosamide in TNBC management.
三阴性乳腺癌（TNBC）是最难治疗的乳腺癌之一，因为它没有靶向治疗方法，对于TNBC患者，常规的细胞毒性化疗后辅助放疗是标准治疗方案。我们在此报告，电离辐射（IR）可诱导TNBC的MDA-MB-231、MDA-MB-468和Hs578T细胞中Wnt3a、LRP6和β-连环蛋白的表达，并因此激活Wnt/β-连环蛋白信号通路。此外，通过短发夹RNA（shRNA）耗尽β-连环蛋白可使TNBC细胞对IR敏感，而Wnt3a蛋白处理或β-连环蛋白过表达则导致TNBC细胞产生放射抗性。尼克索酰胺是一种有效的Wnt/β-连环蛋白信号通路抑制剂，它不仅抑制组成型Wnt/β-连环蛋白信号通路，还能阻断IR诱导的TNBC细胞中的Wnt/β-连环蛋白信号通路。此外，尼克索酰胺可使TNBC细胞对IR敏感，防止Wnt3a诱导的放射抗性，并克服TNBC细胞中β-连环蛋白诱导的放射抗性。重要的是，与单独进行局部肿瘤照射相比，接受尼克索酰胺和γ射线局部肿瘤照射联合治疗的动物，其MDA-MB-231肿瘤生长受到显著抑制。这些发现表明，Wnt/β-连环蛋白信号通路在TNBC细胞放射抗性的发展中起重要作用，并且尼克索酰胺通过抑制TNBC细胞中的Wnt/β-连环蛋白信号通路具有显著的放射增敏作用。我们的研究还为尼克索酰胺在TNBC治疗中的进一步临床前和临床评估提供了理论依据。
