Targeting SOST using a small-molecule compound retards breast cancer bone metastasis.
Targeting SOST using a small-molecule compound retards breast cancer bone metastasis.
复制标题
使用小分子化合物靶向 SOST 可延缓乳腺癌骨转移
DOI：
10.1186/s12943-022-01697-4
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发表时间：
2022-12-29
期刊：
影响因子：
37.3
通讯作者：
Liu, Caigang
中科院分区：
文献类型：
--
作者：
Sun, Lisha;Zhang, Yixiao;Chen, Guanglei;Ji, Yaoting;Ma, Qingtian;Qiao, Xinbo;Wu, Sijin;Zhou, Lin;Bu, Jiawen;Zhu, Xudong;Zhang, Xiaoying;Jiang, Xiaofan;Liu, Chao;Li, Xinnan;Liu, Yang;Yang, Yongliang;Liu, Caigang
乳腺癌骨转移可因骨质疏松而加重，与较差的长期生存率相关，并且治疗选择有限。硬化蛋白（SOST）是一种内源性骨形成抑制剂，是治疗骨质疏松症的一个有吸引力的靶点。然而，SOST能否作为乳腺癌骨转移的治疗靶点，以及靶向乳腺癌细胞中SOST的小分子化合物能否抑制乳腺癌骨转移，目前尚不清楚。方法对442例乳腺癌组织中ssost的表达进行免疫组化分析，并对其与乳腺癌骨转移的关系进行统计学分析。通过诱导骨转移性乳腺癌SCP2细胞沉默或过表达SOST，在体外和体内检测其骨转移行为。为了确定潜在的治疗方法，我们从一个小化学分子文库中筛选了SOST与STAT3相互作用的抑制剂，并在体外和体内测试了一种抑制剂对乳腺癌生长和骨转移的抑制作用。结果SOST表达上调与乳腺癌骨转移及乳腺癌患者生存率降低有关。SOST沉默显著降低了SCP2细胞的骨转移能力。SOST与STAT3相互作用，增强TGF-β/KRAS信号，促进肿瘤生长和骨转移。用一种主要候选药物S6治疗可显著抑制小鼠乳腺癌类器官的生长和骨转移。结论我们的发现为治疗乳腺癌骨转移提供了一种新的治疗方法。
BackgroundBreast cancer metastasis to the bone can be exacerbated by osteoporosis, is associated with poor long-term survival, and has limited therapeutic options. Sclerostin (SOST) is an endogenous inhibitor of bone formation, and an attractive target for treatment of osteoporosis. However, it is unclear whether SOST can be used as a therapeutic target for bone metastases of breast cancer, and whether small molecule compounds that target SOST in breast cancer cells can inhibit breast cancer bone metastasis.MethodsSOST expression in 442 breast cancer tissues was characterized by immunohistochemistry and statistically analyzed for the association with breast cancer bone metastases. Bone metastatic breast cancer SCP2 cells were induced for SOST silencing or overexpression and their bone metastatic behaviors were tested in vitro and in vivo. To identify potential therapeutics, we screened inhibitors of the interaction of SOST with STAT3 from a small chemical molecule library and tested the inhibitory effects of one inhibitor on breast cancer growth and bone metastasis in vitro and in vivo.ResultsWe found that up-regulated SOST expression was associated with breast cancer bone metastases and worse survival of breast cancer patients. SOST silencing significantly reduced the bone metastatic capacity of SCP2 cells. SOST interacted with STAT3 to enhance the TGF-β/KRAS signaling, increasing both tumor growth and bone metastasis. Treatment with one lead candidate, S6, significantly inhibited the growth of breast-cancer organoids and bone metastasis in mice.ConclusionsOur findings highlight a new class of potential therapeutics for treatment of bone metastasis in breast cancer.
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