SOX9 Regulates Low Density Lipoprotein Receptor-related Protein 6 (LRP6) and T-cell Factor 4 (TCF4) Expression and Wnt/β-catenin Activation in Breast Cancer

Gene expression profiling has identified breast cancer (BCa) subtypes, including an aggressive basal-like (BL) subtype. The molecular signals underlying the behavior observed in BL-BCa group are largely unknown, although recent results indicate a prevalent increase in Wnt/β-catenin activity. Our immunohistochemistry study confirmed that SOX9, one of the BL-BCa signature genes, was expressed by most BL-BCa, and its expression correlated with indicators of poor prognosis. Importantly, BCa gene expression profiling strongly associated SOX9 with the expression of Wnt/β-catenin pathway components, LRP6 and TCF4. In cancer cell lines, SOX9 silencing reduced cell proliferation and invasion, LRP6 and TCF4 transcription, and decreased Wnt/β-catenin activation. SOX9 expression was also increased by Wnt, indicating that SOX9 is at the center of a positive feedback loop that enhances Wnt/β-catenin signaling. Consistently, SOX9 overexpression in BCa cell lines and transgenic SOX9 expression in breast epithelium caused increased LRP6 and TCF4 expression and Wnt/β-catenin activation. These results identify SOX9-mediated Wnt/β-catenin activation as one of the molecular mechanisms underlying aberrant Wnt/β-catenin activity in BCa, especially in the BL-BCa subgroup. Background: Mechanism of enhanced Wnt/β-catenin activation in breast cancer (BCa) is not fully characterized. Results: SOX9 was highly expressed in basal-like BCa. SOX9 maintained and enhanced LRP6 and TCF4 transcription and Wnt/β-catenin activation in vitro and in vivo . Conclusion: SOX9 supports a positive feedback loop to sustain Wnt/β-catenin signal. Significance: The results reveal a new mechanism of Wnt/β-catenin pathway activation in BCa.