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

Lisha Sun, Yixiao Zhang, Guanglei Chen, Yaoting Ji, Qingtian Ma, Xinbo Qiao, Sijin Wu*, Lin Zhou, Jiawen Bu, Xudong Zhu, Xiaoying Zhang, Xiaofan Jiang, Chao Liu, Xinnan Li, Yang Liu, Yongliang Yang, Caigang Liu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: Our findings highlight a new class of potential therapeutics for treatment of bone metastasis in breast cancer.

Original languageEnglish
Article number228
JournalMolecular Cancer
Volume21
Issue number1
DOIs
Publication statusPublished - Dec 2022
Externally publishedYes

Keywords

  • Bone metastasis
  • Breast cancer
  • SOST
  • Small-molecule compound

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