Abstract B044: Intracellular sclerostin plays a vital role in tumor progression and metastasis in triple-negative breast cancer

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Abstract Background: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with limited treatment options. It is essential to continue advancing well-defined molecular targets in TNBC. Sclerostin (SOST) is mostly concerned as an osteocyte secreted protein and a drug target for osteoporosis. Recently, sclerostin was reported to be expressed in a majority of clinical TNBC tissues. Upregulated SOST expression was reported to be associated with worse prognosis in breast cancer patients. This study aimed to investigate the role of sclerostin in TNBC. Methods: Cell proliferative ability was evaluated by colony formation assay. Cell migratory and invasive abilities were evaluated by transwell assay. The tumor growth and metastasis were evaluated in 4T1 orthotopic and metastatic mouse models. The cellular uptake of antibody and aptamer was evaluated by fluorescence microscopy. Results: It was found that sclerostin knockout demonstrated inhibitory effects on proliferation and migration/invasion in both human (MDA-MB-231) and murine (4T1) TNBC cell lines in vitro. Surprisingly, no tumor growth and metastasis were found in 4T1-sost KO inoculated orthotopic and metastatic mouse models compared to their wildtype counterparts. It suggested the vital role of sclerostin in TNBC. Anti-sclerostin antibody (Scl-Ab) could not be internalized by TNBC cells and demonstrated no effects on proliferation and migration/invasion in vitro. On the other hand, no difference in proliferation and migration/invasion was also observed between TNBC cells with and without supplementing sclerostin in vitro. Genetically, there was no difference in tumor growth between 4T1 inoculated WT mice and SOST -/− mice. Pharmacologically, no difference was also observed in tumor growth between Scl-Ab treatment and IgG control in 4T1 inoculated mice. It suggested that the role of extracellular and systemic sclerostin could be excluded in TNBC. Aptamers are single-strand nucleic acids which bind to specific targets. It was found that sclerostin-specific aptamer (Scl-Ap) could be internalized by TNBC cells and demonstrated inhibitory effects on proliferation and migration in vitro. Consistently, Scl-Ap demonstrated inhibitory effects on tumor growth in 4T1 inoculated mice. It suggested that intracellular sclerostin might play a vital role in TNBC. Conclusions: Intracellular sclerostin plays a vital role in TNBC progression and metastasis. Citation Format: Meiheng SUN, Shuangying Qiao, Hang Luo, Xin Yang, Liu Yang, Huarui Zhang, Zefeng Chen, Luyao Wang, Xiaohui Tao, Yuanyuan Yu, Yuan Ma, Fenglai Yuan, Daqing Ma, Qianjun Chen, Aiping Lu, Bao-ting Zhang, Ge Zhang, Fangfei Li. Intracellular sclerostin plays a vital role in tumor progression and metastasis in triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B044.

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