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

Oncogene volume 25, pages 4361–4369 (2006)Cite this article

Abstract

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

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Acknowledgements

We thank Mickey Williams and Jane Winer for help in performing microarray analysis, Bonnee Rubinfeld for helpful discussion and Bill Forrest for help with statistical analysis.

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Authors and Affiliations

  1. Department of Molecular Oncology, Genentech Inc., South San Francisco, CA, USA

    M Shulewitz, I Soloviev, P Polakis & C Sakanaka

  2. Department of Bioinformatics, Genentech Inc., South San Francisco, CA, USA

    T Wu

  3. Department of Pathology, Genentech Inc., South San Francisco, CA, USA

    H Koeppen

Authors
  1. M Shulewitz
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  2. I Soloviev
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  3. T Wu
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  4. H Koeppen
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  5. P Polakis
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  6. C Sakanaka
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Correspondence to C Sakanaka.

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Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc).

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Shulewitz, M., Soloviev, I., Wu, T. et al. Repressor roles for TCF-4 and Sfrp1 in Wnt signaling in breast cancer. Oncogene 25, 4361–4369 (2006). https://doi.org/10.1038/sj.onc.1209470

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  • DOI: https://doi.org/10.1038/sj.onc.1209470

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