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  • Original Paper
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Stabilization of β-catenin induces lesions reminiscent of prostatic intraepithelial neoplasia, but terminal squamous transdifferentiation of other secretory epithelia

Oncogene volume 21, pages 4099–4107 (2002)Cite this article

Abstract

The present study documents that stabilization of β-catenin is sufficient to induce lesions reminiscent of prostate intraepithelial neoplasia (PIN). Such lesions were present in all compound mutant mice and all prostate acini expressing stabilized β-catenin. High grade PIN-like lesions resembling early human prostate cancer were detected as early as 10 weeks of age. Surprisingly, stabilization of β-catenin in other secretory epithelia including salivary, preputial, harderian, and mammary glands induced extensive squamous metaplasia and keratinization associated with terminal differentiation of the target cells, but failed to cause neoplastic transformation. Epidermal hyperplasia, hair follicle cysts, and odontomas were also observed. The prostatic lesions exhibited upregulation of c-myc, increased rate of cellular proliferation, loss of the Na-K-Cl co-transporter NKCC1, and expression of androgen receptor. Basal cell markers such as p63 and keratin 5 were not expressed by the masses of PIN-like lesions, but were present in small foci of proliferating β-catenin expressing basal cells. Our observations indicate that β-catenin stabilization is a crucial event for the initiation of PIN-like lesions, but induces squamous metaplasia rather than tumorigenesis in secretory epithelia other than the prostate.

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Acknowledgements

K Khazaie was supported by the National Colorectal Research Alliance, Dana Farber Cancer Institute, and the Harvard Cancer Center. M Taketo was supported by the Organization for Pharmaceutical Safety and Research (OPSR) and the Ministry of Education, Science, Sports and Culture (MESSC) of Japan. We thank N Harada for the construction of the Catnb +/lox(ex3) mice. K Khazaie is obliged to Robert Mayer, Glenn Dranoff, and Ramesh Shivdasani for their support and encouragement. This work would have not been possible without the advice of Massimo Loda, Lothar Hennighausen, Keiko Miyoshi and Jonathan M Shillingford. Li Zhang and James Dilks are acknowledged for excellent histological service. Eric Smith is acknowledged for expert assistance with recording and presentation of images.

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Authors and Affiliations

  1. Department of Cancer Immunology and Aids, Dana Farber Cancer Institute/Harvard Medical School, Boston, 02115, Massachusetts, MA, USA

    Fotini Gounari, Ludger Klein, Anja Siermann, Harald von Boehmer & Khashayarsha Khazaie

  2. Histo-Pathology Core, Dana Farber Cancer Institute/Harvard Medical School, Boston, 02115, Massachusetts, MA, USA

    Roderick Bronson

  3. Department of Adult Oncology, Dana Farber Cancer Institute/Harvard Medical School, Boston, 02115, Massachusetts, MA, USA

    Sabina Signoretti, William R Sellers & Jennifer Kum

  4. Department of Pathology, Dana Farber Cancer Institute/Harvard Medical School, Boston, 02115, Massachusetts, MA, USA

    Sabina Signoretti, William R Sellers & Jennifer Kum

  5. Department of Pharmacology, Kyoto University Graduate School of Medicine, Sakyo, 606-8501, Kyoto, Japan

    Makoto M Taketo

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  1. Fotini Gounari
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Correspondence to Khashayarsha Khazaie.

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Gounari, F., Signoretti, S., Bronson, R. et al. Stabilization of β-catenin induces lesions reminiscent of prostatic intraepithelial neoplasia, but terminal squamous transdifferentiation of other secretory epithelia. Oncogene 21, 4099–4107 (2002). https://doi.org/10.1038/sj.onc.1205562

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