Abstract C150: SOX9 modulates Wnt/beta-catenin singal in cancer cells by regulating TCF4 and LRP6 expression

Abstract

Abstract Introduction: Cancers frequently exploit developmental genes/pathways to sustain their uncontrolled growth or invasion. SOX9, an important developmental transcription factor is one of the signature genes of the basal-like breast cancers. SOX9 over-expression has been demonstrated in various cancers and is associated with a poor prognosis. In prostate cancer, SOX9 supports tumor proliferation, angiogenesis and local invasion in xenografts. The role of SOX9 as a biomarker and molecular mechanisms of its biological functions were further explored in this study. Methods: Immunohistochmical analysis of SOX9 protein expression was performed on a tissue microarray of 129 breast cancer samples. Gene profiles of the breast cancer samples were examined by ANOVA analysis to identify genes that are expressed at significantly higher level among SOX9-high protein expressing samples. SOX9 regulated genes were validated by their corresponding changes in expression levels to SOX9 silencing in cancer cell lines. The effect of SOX9 silencing on cancer progression was examined in the MCF10A DCIS.com xenografts. Results: SOX9 protein expression was highly represented in the basal-like breast cancers and was associated with poor tumor grades. Among the genes correlated with higher SOX9 expression were two major components of the canonical Wnt/ -catenin signal pathway, ie TCF4 and LRP6. These genes were up- or down-regulated in various cancer cell lines in response to SOX9 overexpression or silencing. More importantly, the Wnt3a induced -catenin activity was significantly reduced when SOX9 protein was specifically down-regulated. SOX9 down-regulation in MCF10A DCIS xenografts lead to a squamous differentiation and a block in the progression from DCIS to invasive carcinoma. Conclusion: This study identified a novel function of SOX9 in modulating Wnt/β-catenin signaling by regulating TCF4 and LRP6 expression. SOX9 enhanced Wnt/β-catenin activity in the absence of APC or β-catenin mutations may play an important role in determining tumor subtype, maintaining tumor stem cells or supporting tumor growth or progression. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C150.