Targeting SOST using a small-molecule compound retards breast cancer bone metastasis

Molecular Cancer

Research

Sijin Wu¹  Xiaoying Zhang²  Chao Liu²  Xinbo Qiao²  Qingtian Ma²  Lisha Sun²  Caigang Liu²  Jiawen Bu²  Xudong Zhu²  Guanglei Chen²  Xiaofan Jiang²  Xinnan Li²  Yixiao Zhang³  Yang Liu⁴  Lin Zhou⁴  Yongliang Yang⁵  Yaoting Ji⁶ 

[1]Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, China

[2]Department of Oncology, Innovative Cancer Drug Research and Engineering Center of Liaoning Province, Cancer Stem Cell and Translation Medicine Lab, Shengjing Hospital of China Medical University, Shenyang, China

[3]Department of Oncology, Innovative Cancer Drug Research and Engineering Center of Liaoning Province, Cancer Stem Cell and Translation Medicine Lab, Shengjing Hospital of China Medical University, Shenyang, China

[4]Department of Urology Surgery, Shengjing Hospital of China Medical University, Shenyang, China

[5]Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China

[6]School of Bioengineering, Dalian University of Technology, Dalian, China

[7]The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China

关键词: SOST;    Bone metastasis;    Breast cancer;    Small-molecule compound;   

DOI  :  10.1186/s12943-022-01697-4

 received in 2022-10-27, accepted in 2022-12-07,  发布年份 2022

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s) 2022

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