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

Oncogene. 2006 Jul 20;25(31):4361-9. doi: 10.1038/sj.onc.1209470. Epub 2006 Mar 13.


Mutations in Wnt pathway genes are rare in human breast cancer, yet activation of the pathway is evident from the misolocalization of beta-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.

MeSH terms

  • Breast Neoplasms / metabolism*
  • Cell Line
  • Cell Line, Tumor
  • Down-Regulation / physiology
  • Female
  • Humans
  • Intercellular Signaling Peptides and Proteins / physiology*
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / physiology*
  • Signal Transduction / physiology*
  • TCF Transcription Factors / antagonists & inhibitors
  • TCF Transcription Factors / physiology*
  • Transcription Factor 7-Like 2 Protein
  • Wnt Proteins / antagonists & inhibitors
  • Wnt Proteins / physiology*


  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • SFRP1 protein, human
  • TCF Transcription Factors
  • TCF7L2 protein, human
  • Transcription Factor 7-Like 2 Protein
  • Wnt Proteins