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Activation of different Wnt/β-catenin signaling components in mammary epithelium induces transdifferentiation and the formation of pilar tumors

Oncogene volume 21, pages 5548–5556 (2002)Cite this article

Abstract

The Wnt/β-catenin signaling pathway controls cell fate and neoplastic transformation. Expression of an endogenous stabilized β-catenin (ΔE3 β-catenin) in mammary epithelium leads to the transdifferentiation into epidermis- and pilar-like structures. Signaling molecules in the canonical Wnt pathway upstream from β-catenin induce glandular tumors but it is not clear whether they also cause squamous transdifferentiation. To address this question we have now investigated mammary epithelium from transgenic mice that express activating molecules of the Wnt pathway: Wnt10b, Int2/Fgf3, CK2α, ΔE3 β-catenin, Cyclin D1, and dominant negative (dn) GSK3β. Cytokeratin 5 (CK5), which is expressed in both mammary myoepithelium and epidermis, and the epidermis-specific CK1 and CK6 were used as differentiation markers. Extensive squamous metaplasias and widespread expression of CK1 and CK6 were observed in ΔE3 β-catenin transgenic mammary tissue. Wnt10b and Int2 transgenes also induced squamous metaplasias, but expression of CK1 and CK6 was sporadic. While CK5 expression in Wnt10b transgenic tissue was still confined to the lining cell layer, its expression in Int2 transgenic tissue was completely disorganized. In contrast, cytokeratin expression in CK2α, dnGSK3β and Cyclin D1 transgenic mammary tissues was similar to that in ΔE3 β-catenin tissue. In support of transdifferentiation, expression of hard keratins specific for hair and nails was observed in pilar tumors. These results demonstrate that the activation of Wnt signaling components in mammary epithelium induces not only glandular tumors but also squamous differentiation, possibly by activating LEF-1, which is expressed in normal mammary epithelium.

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Acknowledgements

We thank Philip Leder for tissue specimen and T-T Sun for the antibody AE13. Part of this work was supported by grants from the Ministry of Education, Science, Sports and Culture and from the Organization for Pharmaceutical Safety and Research, Japan (MM Taketo), by a grant from NIEHS P01 ES11624 (DC Seldin), by a grant from the German Academic Exchange Service (A Rosner) and by grants 5JB-0014 from the State of California Breast Cancer Research Program (RD Cardiff) and U42 RR14905 from the National Institutes of Health, National Centers for Research Resources (RD Cardiff). The authors wish to acknowledge the excellent technical support provided by Judy E Walls.

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Authors and Affiliations

  1. Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, 20892, Maryland, MD, USA

    Keiko Miyoshi, Masahiro Nozawa, Christopher Byrd, Fanta Morgan, Gertraud W Robinson & Lothar Hennighausen

  2. Department of Biochemistry, School of Dentistry, the University of Tokushima, Tokushima, 770–8504, Tokushima, Japan

    Keiko Miyoshi

  3. Center for Comparative Medicine, University of California, Davis, 95616, California, CA, USA

    Andrea Rosner & Robert D Cardiff

  4. Boston Medical Center, Boston, 02118, Massachusetts, MA, USA

    Esther Landesman-Bollag, Xin Xu & David C Seldin

  5. McLaughlin Research Institute, Great Falls, Montana, USA

    Xin Xu

  6. Massachusetts General Hospital, Boston, 02114, Massachusetts, MA, USA

    Emmett V Schmidt

  7. Kyoto University Graduate School of Medicine, Kyoto, Japan

    Makato M Taketo

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  1. Keiko Miyoshi
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  2. Andrea Rosner
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  6. Esther Landesman-Bollag
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  8. David C Seldin
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  9. Emmett V Schmidt
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Correspondence to Lothar Hennighausen.

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Miyoshi, K., Rosner, A., Nozawa, M. et al. Activation of different Wnt/β-catenin signaling components in mammary epithelium induces transdifferentiation and the formation of pilar tumors. Oncogene 21, 5548–5556 (2002). https://doi.org/10.1038/sj.onc.1205686

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  • DOI: https://doi.org/10.1038/sj.onc.1205686

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