Tumour necrosis factor receptor-associated factor 6 (TRAF6) has been implicated in breast cancer and osteoclastic bone destruction. Here, we report that 6877002, a verified small-molecule inhibitor of TRAF6, reduced metastasis, osteolysis and osteoclastogenesis in models of osteotropic human and mouse breast cancer. First, we observed that TRAF6 is highly expressed in osteotropic breast cancer cells and its level of expression was higher in patients with bone metastasis. Pre-exposure of osteoclasts and osteoblasts to non-cytotoxic concentrations of 6877002 inhibited cytokine-induced NFκB activation and osteoclastogenesis, and reduced the ability of osteotropic human MDA-MB-231 and mouse 4T1 breast cancer cells to support bone cell activity. 6877002 inhibited human MDA-MB-231-induced osteolysis in the mouse calvaria organ system, and reduced soft tissue and bone metastases in immuno-competent mice following intra-cardiac injection of mouse 4T1-Luc2 cells. Of clinical relevance, combined administration of 6877002 with Docetaxel reduced metastasis and inhibited osteolytic bone damage in mice bearing 4T1-Luc2 cells. Thus, TRAF6 inhibitors such as 6877002 – alone or in combination with conventional chemotherapy - show promise for the treatment of metastatic breast cancer.

肿瘤坏死因子受体相关因子6（TRAF6）与乳腺癌和破骨细胞骨破坏有关。在这里，我们报告6870002，一种经过验证的TRAF6小分子抑制剂，可在亲骨性人类和小鼠乳腺癌模型中减少转移，骨溶解和破骨细胞生成。首先，我们观察到TRAF6在亲骨性乳腺癌细胞中高表达，在骨转移患者中其表达水平更高。破骨细胞和成骨细胞暴露于非细胞毒性浓度为6877002之前，抑制了细胞因子诱导的NFκB活化和破骨细胞生成，并降低了趋骨性人类MDA-MB-231和小鼠4T1乳腺癌细胞支持骨细胞活性的能力。6877002在小鼠颅盖器官系统中抑制了人MDA-MB-231诱导的骨溶解，并在心脏内注射小鼠4T1-Luc2细胞后降低了具有免疫能力的小鼠的软组织和骨转移。具有临床意义的是，将6877002与多西他赛联合使用可减少转移瘤并抑制带有4T1-Luc2细胞的小鼠的溶骨性骨损伤。因此，单独或与常规化学疗法联用的TRAF6抑制剂（例如6877002）显示出有望治疗转移性乳腺癌。