Abstract：
Breast 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.
SOST 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.
We 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.
Our findings highlight a new class of potential therapeutics for treatment of bone metastasis in breast cancer.
SOST 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.
We 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.
Our findings highlight a new class of potential therapeutics for treatment of bone metastasis in breast cancer.
摘要：
背景：骨质疏松可加剧乳腺癌骨转移，与长期生存率差有关，治疗选择有限。硬骨素(SOST)是骨形成的内源性抑制剂,和治疗骨质疏松症的一个有吸引力的目标。然而,目前尚不清楚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SOST的小分子化合物能否抑制乳腺癌骨转移。
方法：对442例乳腺癌组织中SOST的表达进行免疫组化分析，并对其与乳腺癌骨转移的相关性进行统计学分析。诱导骨转移乳腺癌SCP2细胞SOST沉默或过表达，并在体外和体内测试其骨转移行为。为了确定潜在的治疗方法，我们从一个化学小分子库中筛选了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：我们发现SOST表达上调与乳腺癌骨转移和乳腺癌患者生存恶化有关。SOST沉默显著降低SCP2细胞的骨转移能力。SOST与STAT3相互作用以增强TGF-β/KRAS信号传导，增加肿瘤生长和骨转移。与一名主要候选人一起治疗，S6，显着抑制小鼠乳腺癌类器官的生长和骨转移。
结论：我们的发现突出了一类新的治疗乳腺癌骨转移的潜在疗法。
方法：对442例乳腺癌组织中SOST的表达进行免疫组化分析，并对其与乳腺癌骨转移的相关性进行统计学分析。诱导骨转移乳腺癌SCP2细胞SOST沉默或过表达，并在体外和体内测试其骨转移行为。为了确定潜在的治疗方法，我们从一个化学小分子库中筛选了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：我们发现SOST表达上调与乳腺癌骨转移和乳腺癌患者生存恶化有关。SOST沉默显著降低SCP2细胞的骨转移能力。SOST与STAT3相互作用以增强TGF-β/KRAS信号传导，增加肿瘤生长和骨转移。与一名主要候选人一起治疗，S6，显着抑制小鼠乳腺癌类器官的生长和骨转移。
结论：我们的发现突出了一类新的治疗乳腺癌骨转移的潜在疗法。
