Department of Oncology and Metabolism, Medical School, Beech Hill Road, Sheffield, S10 2RX, UK; Department. of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
Department of Oncology and Metabolism, Medical School, Beech Hill Road, Sheffield, S10 2RX, UK; Bone and Cancer Group, Edinburgh Cancer Research Centre, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XR, UK; Indiana University, IU School of Medicine, Division of Hematology/Oncology, Indianapolis, USA.
Cancer Lett. 2020 Sep 28;488:27-39. doi: 10.1016/j.canlet.2020.05.021. Epub 2020 May 28.
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）已被牵连到乳腺癌和破骨细胞性骨破坏中。在这里，我们报告称，6877002，一种经证实的 TRAF6 小分子抑制剂，可减少亲骨性人源和鼠源乳腺癌模型中的转移、骨质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度表达，并且其表达水平在发生骨转移的患者中更高。预先暴露于破骨细胞和成骨细胞中非细胞毒性浓度的 6877002 可抑制细胞因子诱导的 NFκB 激活和破骨细胞生成，并降低亲骨性人源 MDA-MB-231 和鼠源 4T1 乳腺癌细胞支持骨细胞活性的能力。6877002 抑制人源 MDA-MB-231 在小鼠颅骨器官系统中诱导的骨质溶解，并在免疫活性小鼠心脏内注射鼠源 4T1-Luc2 细胞后减少软组织和骨转移。具有临床相关性的是，6877002 与多西他赛联合给药可减少携带 4T1-Luc2 细胞的小鼠的转移并抑制溶骨性骨损伤。因此，TRAF6 抑制剂（如 6877002）——单独或与常规化疗联合使用——有望用于治疗转移性乳腺癌。
