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Targeting SOST using a small-molecule compound retards breast cancer bone metastasis
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...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9798707/ https://www.ncbi.nlm.nih.gov/pubmed/36581888 http://dx.doi.org/10.1186/s12943-022-01697-4 |
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author | 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 |
author_facet | 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 |
author_sort | Sun, Lisha |
collection | PubMed |
description | 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12943-022-01697-4. |
format | Online Article Text |
id | pubmed-9798707 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-97987072022-12-30 Targeting SOST using a small-molecule compound retards breast cancer bone metastasis 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 Mol Cancer Research 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12943-022-01697-4. BioMed Central 2022-12-29 /pmc/articles/PMC9798707/ /pubmed/36581888 http://dx.doi.org/10.1186/s12943-022-01697-4 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research 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 Targeting SOST using a small-molecule compound retards breast cancer bone metastasis |
title | Targeting SOST using a small-molecule compound retards breast cancer bone metastasis |
title_full | Targeting SOST using a small-molecule compound retards breast cancer bone metastasis |
title_fullStr | Targeting SOST using a small-molecule compound retards breast cancer bone metastasis |
title_full_unstemmed | Targeting SOST using a small-molecule compound retards breast cancer bone metastasis |
title_short | Targeting SOST using a small-molecule compound retards breast cancer bone metastasis |
title_sort | targeting sost using a small-molecule compound retards breast cancer bone metastasis |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9798707/ https://www.ncbi.nlm.nih.gov/pubmed/36581888 http://dx.doi.org/10.1186/s12943-022-01697-4 |
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