1. ¹Department of Molecular Oncology, Genentech Inc., South San Francisco, CA, USA
2. ²Department of Bioinformatics, Genentech Inc., South San Francisco, CA, USA
3. ³Department of Pathology, Genentech Inc., South San Francisco, CA, USA

Correspondence: Dr C Sakanaka, Department of Molecular Oncology, Genentech Inc, 1 DNA Way, MS40, South San Francisco, CA 94080, USA. E-mail: chies@gene.com

Received 21 June 2005; Revised 1 December 2005; Accepted 18 January 2006; Published online 13 March 2006.

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.