Abstract C12: Beta-catenin enhances synovial sarcomagenesis and provides a therapeutic target.

Abstract

Abstract β-catenin is a master regulator in the cellular biology of development and neoplasia. Its dysregulation is implicated as a driver of colorectal carcinogenesis and the epithelial-mesenchymal transition in other cancers. Nuclear β-catenin is known to be a poor prognostic sign in synovial sarcoma, the most common soft-tissue sarcoma in adolescents and young adults. Beyond this prognostic correlation, the biology of β-catenin's role in synovial sarcoma has not been explored. We show through genetic experiments in mice demonstrate that loss of β-catenin hampers SS18-SSX2-driven synovial sarcomagenesis. Expression of a stabilized form of β-catenin greatly enhances synovial sarcomagenesis. Stabilization of β-catenin specifically enables transformation under the influence of the SS18-SSX2 fusion oncogene by blocking differentiation and apoptosis. As part of the mechanism of this impact, β-catenin recruits BRG1-containing SWI/SNF chromatin remodeling complexes to activated target genes. Compounds disrupting the transcriptional activity of β-catenin are toxic to human and mouse synovial sarcoma cell lines. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C12. Citation Format: Kevin B. Jones, Benjamin Illum, Huifeng Jin, Julie Zhu Mu, Michael Monument, Allie Grossmann, Mario R. Capecchi. Beta-catenin enhances synovial sarcomagenesis and provides a therapeutic target. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C12.