LAUSR

Background: Triple-negative breast cancers (TNBCs) are the most aggressive breast cancers and have a very poor prognosis. Since TNBCs lack the expression of the estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2), and progesterone receptor (PR), development of new TNBC treatment strategies is an urgent clinical need. Our previous studies have demonstrated that high expression and activity of SOX9 transcription factor positively related to TNBC cell growth and tumor metastasis in vivo. It may be possible to target the SOX9 transcription factor by targeting upstream SOX9-activating proteins. Hypothesis: SOX9-binding protein, S100A10, regulates SOX9 activity and control TNBC growth. Material and Methods: Immunoprecipitation (IP) in combination with mass spectrometry (IP-MS) analysis was used to identify SOX9 binding proteins, with support from MD Anderson’s proteomics core. The Mascot Score is a statistical score used as a measure of the reliability of identifying a specific protein by IP-MS. The data was summarized based on the Mascot Score. IP-Western Blotting analysis was used to confirm that S100A10 bound SOX9 in TNBC cells. We then treated TNBC cells with or without siRNAs of S100A10 to evaluate its effect on TNBC growth. Cell growth was measured using an automated cell counting assay. Protein and mRNA levels were examined by western blotting and qRT-PCR assays. SOX9 activity on regulating β-catenin pathway was measured using TOP/FOP luciferase activity analysis. Data are presented as mean values ± SD. Statistical significance was calculated using the Student’s t-test unless otherwise indicated. Results: Using immunoprecipitation combined with mass spectrometry (IP-MS), we identified multiple SOX9-binding proteins. One of the identified SOX9-binding proteins was S100A10 (S100A10). Knockdown of S100A10 decreased TNBC cell growth in vitro. Using TOP/FOP luciferase activity analysis, we demonstrated that S100A10 regulates the β-catenin pathway. Thus, S100A10 is a potential activator of SOX9 that can be targeted to inhibit SOX9 downstream signaling and TNBC growth. Conclusion: Our results demonstrate that S100A10 is a SOX9-binding protein, that regulates SOX9 downstream signaling and controls TNBC cell growth. Implications: Inhibition of S100A10 represents a novel strategy to treat TNBCs. S100A10 inhibitors should be developed as promising new drugs to treat these aggressive breast cancers. Grant Support: These studies were supported by a Breast Cancer Research Foundation (BCRF) grant (PB). The Proteomics and Metabolomics Facility was supported in part by Cancer Prevention Research Institute of Texas (CPRIT) grant number RP130397 and NIH grant numbers 1S10OD012304-01 and P30CA016672. Citation Format: Yanxia Ma, Jing Qian, Cassandra Moyer, Amanda Lanier, Jamal Hill, Darian Coleman, David H. Hawke, Abhijit Mazumdar, Powel H. Brown. Targeting S100A10, a SOX9 binding protein, for the treatment of triple negative breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3966.