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Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in patched heterozygous knockout mice

Nature Medicine volume 5, pages 1285–1291 (1999)Cite this article

Abstract

Basal cell carcinomas, the commonest human skin cancers, consistently have abnormalities of the hedgehog signaling pathway and often have PTCH gene mutations. We report here that Ptch+/– mice develop primordial follicular neoplasms resembling human trichoblastomas, and that exposure to ultraviolet radiation or ionizing radiation results in an increase in the number and size of these tumors and a shift in their histologic features so that they more closely resemble human basal cell carcinoma. The mouse basal cell carcinomas and trichoblastoma-like tumors resemble human basal cell carcinomas in their loss of normal hemidesmosomal components, presence of p53 mutations, frequent loss of the normal remaining Ptch allele, and activation of hedgehog target gene transcription. The Ptch mutant mice provide the first mouse model, to our knowledge, of ultraviolet and ionizing radiation-induced basal cell carcinoma-like tumors, and also demonstrate that Ptch inactivation and hedgehog target gene activation are essential for basal cell carcinoma tumorigenesis.

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Figure 1: Gross and histopathological findings.
Figure 2: BCC-like tumor average cross-sectional area increases with duration of UV exposure and dose of IR exposure.
Figure 3: In situ detection of hedgehog target genes and immunohistology of Ptch+/– mouse BCC differentiation markers, hemidesmosomal proteins and Bcl2 protein.

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Acknowledgements

We thank L. Goodrich for providing the Ptch +/– mouse, M. Weinstein and S. Pennypacker for technical assistance, and R. Szabo for his critical input. This work was supported by grants from the National Institutes of Health (AR39959, AR4311 and CA81888) (E.H.E.), fellowships from the Dermatology Foundation (M.A.), and donations from P. Hughes and from the Michael J. Rainen Family Foundation. M.P.S. is an Investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Department of Dermatology, University of California San Francisco, Building 100, Room 269, 1001 Potrero Ave, San Francisco, 94110, California, USA

    Michelle Aszterbaum, John Epstein, Vanja Douglas & Ervin H. Epstein Jr.

  2. Department of Dermatology, Stanford University, P210, 1201 Welch Road, Stanford, 94305, California, USA

    Anthony Oro

  3. Department of Dermatology and Pathology, University of California San Francisco, 1701 Divisadero Ave, San Francisco, 94115, California, USA

    Philip E. LeBoit

  4. Departments of Developmental Biology and Genetics and Howard Hughes Medical Institute, Stanford University School of Medicine, 279 Campus Drive, Stanford, A94305, California, USA

    Matthew P. Scott

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  1. Michelle Aszterbaum
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Correspondence to Matthew P. Scott or Ervin H. Epstein Jr..

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Aszterbaum, M., Epstein, J., Oro, A. et al. Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in patched heterozygous knockout mice. Nat Med 5, 1285–1291 (1999). https://doi.org/10.1038/15242

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