JCI Insight. 2019 Feb 21;4(4). doi: 10.1172/jci.insight.125138.
Dormant cancer cells known as disseminated tumor cells (DTCs) are often present in bone marrow of breast cancer patients. These DTCs are thought to be responsible for the incurable recurrence of breast cancer. The mechanism underlying the long-term maintenance of DTCs remains unclear, however. Here, we show that Fbxw7 is essential for the maintenance of breast cancer dormancy. Genetic ablation of Fbxw7 in breast cancer cells disrupted the quiescence of DTCs, rendering them proliferative, in mouse xenograft and allograft models. Fbxw7-deficient DTCs were significantly depleted by treatment with paclitaxel, suggesting that cell proliferation induced by Fbxw7 ablation sensitized DTCs to chemotherapy. The combination of Fbxw7 ablation and chemotherapy reduced the number of DTCs even when applied after tumor cell dissemination. Mice injected with Fbxw7-deficient cancer cells survived longer after tumor resection and subsequent chemotherapy than did those injected with wild-type cells. Furthermore, database analysis revealed that breast cancer patients whose tumors expressed FBXW7 at a high level had a poorer prognosis than did those with a low FBXW7 expression level. Our results suggest that a wake-up strategy for DTCs based on Fbxw7 inhibition might be of value in combination with conventional chemotherapy for the treatment of breast cancer.
休眠癌细胞又称为播散性肿瘤细胞（DTCs），常存在于乳腺癌患者的骨髓中。这些 DTCs 被认为是导致乳腺癌不可治愈复发的原因。然而，DTC 长期维持的机制尚不清楚。在这里，我们发现 Fbxw7 对于维持乳腺癌休眠状态至关重要。在乳腺癌细胞中敲除 Fbxw7 基因会破坏 DTC 的静止状态，使其在小鼠异种移植和同种异体移植模型中增殖。用紫杉醇处理可显著减少 Fbxw7 缺陷型 DTC，这表明 Fbxw7 缺失诱导的细胞增殖使 DTC 对化疗敏感。即使在肿瘤细胞播散后应用 Fbxw7 缺失和化疗的联合治疗，也能减少 DTC 的数量。与注射野生型细胞的小鼠相比，接受 Fbxw7 缺失的癌细胞注射的小鼠在肿瘤切除和随后的化疗后存活时间更长。此外，数据库分析显示，肿瘤中 FBXW7 高表达的乳腺癌患者预后比 FBXW7 低表达的患者差。我们的研究结果表明，基于 Fbxw7 抑制的 DTC 唤醒策略可能与传统化疗联合用于治疗乳腺癌具有重要价值。
