Repressor roles for TCF-4 and Sfrp1 in Wnt signaling in breast cancer

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Abstract
Mutations in Wnt pathway genes are rare in human breast cancer, yet activation of the pathway is evident from the misolocalization of -catenin. We searched for relationships in the expression of Wnt pathway genes and found that both secreted frizzled related protein 1 (Sfrp1) and TCF-4 transcripts were all highly downregulated in a common subset of breast cancers relative to normal breast tissue. Sfrp1 has been previously characterized as a Wnt inhibitor, and we found that interfering with its expression in the human mammary epithelial cell line MCF10A activated Wnt signaling. Reduction of TCF-4 levels in breast cancer was surprising as it is a transcription factor that is responsive to Wnt signaling. Therefore, we investigated a possible inhibitory role for TCF-4 in human breast cells as well as further characterizing Sfrp1. We identified CD24 as a Wnt target in MCF10A cells and used its expression a marker of Wnt signaling. Interfering with either Sfrp1 or TCF-4 in this cell line enhanced CD24 expression. Furthermore, removal of TCF/LEF binding sites in a CD24-luciferase reporter resulted in elevated reporter gene expression. Our results indicate that both Sfrp1 and TCF-4 repress Wnt signaling in breast tissue and their downregulation contributes to the activation of Wnt signaling.