Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Basal cell carcinomas: attack of the hedgehog

Key Points

  • Basal cell carcinomas (BCCs) are keratinocyte tumours that resemble the basal layer of the epidermis, and are the most commonly diagnosed human cancer among persons of European ancestry.

  • Despite this high frequency, the death rate is extraordinarily low, a reflection perhaps of the excellent care provided by physicians and of their vanishingly rare propensity to metastasize.

  • The vast majority of BCCs occur sporadically, but patients with the rare heritable disorder basal cell nevus syndrome (BCNS) have a marked susceptibility to developing BCCs.

  • Family based linkage studies of kindreds with BCNS identified the patched 1 (PTCH1) gene, an inhibitor of the hedgehog signalling pathway, as being mutated in these patients. p53 is also mutated in some patients with sporadic BCCs.

  • Downstream signalling pathways that are deregulated in patients with BCCs are currently being investigated.

  • Surgery is curative for most patients with BCCs. However, for those few that develop locally advanced or metastatic BCC, for which there is currently no effective treatment, Phase I clinical trials with inhibitors of the hedgehog signalling pathway have produced promising results.

Abstract

Basal cell carcinomas (BCCs) were essentially a molecular 'black box' until some 12 years ago, when identification of a genetic flaw in a rare subset of patients who have a great propensity to develop BCCs pointed to aberrant Hedgehog signalling as the pivotal defect leading to formation of these tumours. This discovery has facilitated a remarkable increase in our understanding of BCC carcinogenesis and has highlighted the carcinogenic role of this developmental pathway when aberrantly activated in adulthood. Importantly, a phase 1 first-in-human trial of a Hedgehog inhibitor has shown real progress in halting and even reversing the growth of these tumours.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Histological sections of basal cell carcinoma and squamous cell carcinoma of the skin.
Figure 2: The cutaneous appearance of basal cell carcinoma.
Figure 3: A basic schematic of the Hedgehog (HH) signalling pathway.

Similar content being viewed by others

References

  1. Miller, D. L. Nonmelanoma skin cancer in the United States: incidence. J. Am. Acad. Dermatol. 30, 774–778 (1994).

    Article  CAS  PubMed  Google Scholar 

  2. Housman, T. S. et al. Skin cancer is among the most costly of all cancers to treat for the Medicare population. J. Am. Acad. Dermatol. 48, 425–429 (2003).

    Article  PubMed  Google Scholar 

  3. Rubin, A. I., Chen, E. H. & Ratner, D. Basal-cell carcinoma. N. Eng. J. Med. 353, 2262–2269 (2005). This paper gives an authoritative, more complete review of the more clinical aspects of this tumour.

    Article  CAS  Google Scholar 

  4. Karagas, M. R. et al. Use of tanning devices and risk of basal cell and squamous cell skin cancers. J. Natl Cancer Inst. 94, 224–226 (2002).

    Article  PubMed  Google Scholar 

  5. Marcil, I. & Stern, R. S. Risk of developing a subsequent nonmelanoma skin cancer in patients with a history of nonmelanoma skin cancer: a critical review of the literature and meta-analysis. Arch. Dermatol. 136, 1524–1530 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Karagas, M. R. et al. Risk of subsequent basal cell carcinoma and squamous cell carcinoma of the skin among patients with prior skin cancer. JAMA 267, 3305–3310 (1992).

    Article  CAS  PubMed  Google Scholar 

  7. Chuang, T. Y., Reizner, G. T., Elpern, D. J., Stone, J. L. & Farmer, E. R. Nonmelanoma skin cancer in Japanese ethnic Hawaiians in Kauai, Hawaii: an incidence report. J. Am. Acad. Dermatol. 33, 422–426 (1995).

    Article  CAS  PubMed  Google Scholar 

  8. Chuang, T. Y., Reizner, G. T., Elpern, D. J., Stone, J. L. & Farmer, E. R. Non-melanoma skin cancer and keratoacanthoma in Filipinos: an incidence report from Kauai, Hawaii. Int. J. Dermatol. 32, 717–718 (1993).

    Article  CAS  PubMed  Google Scholar 

  9. Hoshida, Y. et al. Cancer risk after renal transplantation in Japan. Int. J. Cancer 71, 517–520 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Kricker, A., Armstrong, B. K., English, D. R. & Heenan, P. J. Does intermittent sun exposure cause basal cell carcinoma? A case-control study in Western Australia. Int. J. Cancer 60, 489–494 (1995).

    Article  CAS  PubMed  Google Scholar 

  11. Rosso, S. et al. The multicentre south European study 'Helios'. II: Different sun exposure patterns in the aetiology of basal cell and squamous cell carcinomas of the skin. Br. J. Cancer 73, 1447–1454 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Thompson, S. C., Jolley, D. & Marks, R. Reduction of solar keratoses by regular sunscreen use. N. Engl. J. Med. 329, 1147–1151 (1993).

    Article  CAS  PubMed  Google Scholar 

  13. Pandeya, N., Purdie, D. M., Green, A. & Williams, G. Repeated occurrence of basal cell carcinoma of the skin and multifailure survival analysis: follow-up data from the Nambour Skin Cancer Prevention Trial. Am. J. Epidemiol. 161, 748–754 (2005).

    Article  PubMed  Google Scholar 

  14. van der Pols, J. C., Williams, G. M., Pandeya, N., Logan, V. & Green, A. C. Prolonged prevention of squamous cell carcinoma of the skin by regular sunscreen use. Cancer Epidemiol. Biomarkers Prev. 15, 2546–2548 (2006).

    Article  PubMed  Google Scholar 

  15. Kricker, A., Armstrong, B. K., English, D. R. & Heenan, P. J. A dose-response curve for sun exposure and basal cell carcinoma. Int. J. Cancer 60, 482–488 (1995).

    Article  CAS  PubMed  Google Scholar 

  16. Guo, H. R., Yu, H. S., Hu, H. & Monson, R. R. Arsenic in drinking water and skin cancers: cell-type specificity (Taiwan, ROC). Cancer Causes Control 12, 909–916 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Karagas, M. R. et al. Skin cancer risk in relation to toenail arsenic concentrations in a US population-based case-control study. Am. J. Epidemiol. 153, 559–565 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Karagas, M. R., Stukel, T. A. & Tosteson, T. D. Assessment of cancer risk and environmental levels of arsenic in New Hampshire. Int. J. Hyg. Environ. Health 205, 85–94 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Gailani, M. R. et al. Developmental defects in Gorlin syndrome related to a putative tumor suppressor gene on chromosome 9. Cell 69, 111–117 (1992).

    Article  CAS  PubMed  Google Scholar 

  20. Hahn, H. et al. Mutations of the human homologue of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 85, 841–851 (1996).

    Article  CAS  PubMed  Google Scholar 

  21. Johnson, R. L. et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272, 1668–1671 (1996). References 19–21 provide the original data linking basal cell carcinogenesis to aberrant activation of HH signalling.

    Article  CAS  PubMed  Google Scholar 

  22. Klein, R. D., Dykas, D. J. & Bale, A. E. Clinical testing for the nevoid basal cell carcinoma syndrome in a DNA diagnostic laboratory. Genet. Med. 7, 611–619 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Ling, G. et al. PATCHED and p53 gene alterations in sporadic and hereditary basal cell cancer. Oncogene 20, 7770–7778 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Ouhtit, A. et al. UV-radiation-specific p53 mutation frequency in normal skin as a predictor of risk of basal cell carcinoma. J. Natl Cancer Inst. 90, 523–531 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. Hutchin, M. E. et al. Sustained Hedgehog signaling is required for basal cell carcinoma proliferation and survival: conditional skin tumorigenesis recapitulates the hair growth cycle. Genes Dev. 19, 214–223 (2005). This paper illustrates the requirement for continued HH signalling for BCC maintenance in a murine model of HH-driven BCC carcinogenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Adolphe, C., Hetherington, R., Ellis, T. & Wainwright, B. Patched1 functions as a gatekeeper by promoting cell cycle progression. Cancer Res. 66, 2081–2088 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Gailani, M. R. et al. The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nature Genet. 14, 78–81 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Aszterbaum, M. et al. Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome. J. Invest. Dermatol. 110, 885–888 (1998).

    Article  CAS  PubMed  Google Scholar 

  29. Xie, J. et al. Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 391, 90–92 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Reifenberger, J. et al. Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res. 58, 1798–1803 (1998).

    CAS  PubMed  Google Scholar 

  31. Lum, L. & Beachy, P. A. The Hedgehog response network: sensors, switches, and routers. Science 304, 1755–1759 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Rohatgi, R. & Scott, M. P. Patching the gaps in Hedgehog signalling. Nature Cell Biol. 9, 1005–1009 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Varjosalo, M. & Taipale, J. Hedgehog signaling. J. Cell Sci. 120, 3–6 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Kinzler, K. W. et al. Identification of an amplified, highly expressed gene in a human glioma. Science 236, 70–73 (1987).

    Article  CAS  PubMed  Google Scholar 

  35. Bhatia, N. et al. Gli2 is targeted for ubiquitination and degradation by β-TrCP ubiquitin ligase. J. Biol. Chem. 281, 19320–19326 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Huntzicker, E. G. et al. Dual degradation signals control Gli protein stability and tumor formation. Genes Dev. 20, 276–281 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jiang, J. Regulation of Hh/Gli signaling by dual ubiquitin pathways. Cell Cycle 5, 2457–2463 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Pan, Y., Bai, C. B., Joyner, A. L. & Wang, B. Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation. Mol. Cell. Biol. 26, 3365–3377 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Huangfu, D. et al. Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426, 83–87 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Huangfu, D. & Anderson, K. V. Cilia and Hedgehog responsiveness in the mouse. Proc. Natl Acad. Sci. USA 102, 11325–11330 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Corbit, K. C. et al. Vertebrate Smoothened functions at the primary cilium. Nature 437, 1018–1021 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. May, S. R. et al. Loss of the retrograde motor for IFT disrupts localization of Smo to cilia and prevents the expression of both activator and repressor functions of Gli. Dev. Biol. 287, 378–389 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Rohatgi, R., Milenkovic, L. & Scott, M. P. Patched1 regulates hedgehog signaling at the primary cilium. Science 317, 372–376 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Bonifas, J. M. et al. Activation of expression of hedgehog target genes in basal cell carcinomas. J. Invest. Dermatol. 116, 739–742 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Tojo, M., Kiyosawa, H., Iwatsuki, K. & Kaneko, F. Expression of a sonic hedgehog signal transducer, hedgehog-interacting protein, by human basal cell carcinoma. Br. J. Dermatol. 146, 69–73 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Ashton, K. J., Weinstein, S. R., Maguire, D. J. & Griffiths, L. R. Molecular cytogenetic analysis of basal cell carcinoma DNA using comparative genomic hybridization. J. Invest. Dermatol. 117, 683–686 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. Reifenberger, J. et al. Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas. Br. J. Dermatol. 152, 43–51 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Lindstrom, E., Shimokawa, T., Toftgard, R. & Zaphiropoulos, P. G. PTCH mutations: distribution and analyses. Hum. Mutat. 27, 215–219 (2006).

    Article  CAS  PubMed  Google Scholar 

  49. Bodak, N. et al. High levels of patched gene mutations in basal-cell carcinomas from patients with xeroderma pigmentosum. Proc. Natl Acad. Sci. USA 96, 5117–5122 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Daya-Grosjean, L. & Sarasin, A. UV-specific mutations of the human patched gene in basal cell carcinomas from normal individuals and xeroderma pigmentosum patients. Mutat. Res. 450, 193–199 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. Couve-Privat, S., Bouadjar, B., Avril, M. F., Sarasin, A. & Daya-Grosjean, L. Significantly high levels of ultraviolet-specific mutations in the smoothened gene in basal cell carcinomas from DNA repair-deficient xeroderma pigmentosum patients. Cancer Res. 62, 7186–7189 (2002).

    CAS  PubMed  Google Scholar 

  52. Moriwaki, S., Ray, S., Tarone, R. E., Kraemer, K. H. & Grossman, L. The effect of donor age on the processing of UV-damaged DNA by cultured human cells: reduced DNA repair capacity and increased DNA mutability. Mutat. Res. 364, 117–123 (1996).

    Article  PubMed  Google Scholar 

  53. Rees, J. L. The genetics of sun sensitivity in humans. Am. J. Hum. Genet. 75, 739–751 (2004). This remains an authoritative review of genetic factors predisposing to UV-induced skin cancers.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Han, J., Kraft, P., Colditz, G. A., Wong, J. & Hunter, D. J. Melanocortin 1 receptor variants and skin cancer risk. Int. J. Cancer 119, 1976–1984 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Liboutet, M. et al. MC1R and PTCH gene polymorphism in French patients with basal cell carcinomas. J. Invest. Dermatol. 126, 1510–1517 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Box, N. F. et al. Melanocortin-1 receptor genotype is a risk factor for basal and squamous cell carcinoma. J. Invest. Dermatol. 116, 224–229 (2001).

    Article  CAS  PubMed  Google Scholar 

  57. Bastiaens, M. T. et al. Melanocortin-1 receptor gene variants determine the risk of nonmelanoma skin cancer independently of fair skin and red hair. Am. J. Hum. Genet. 68, 884–894 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Gerstenblith, M. R., Goldstein, A. M., Fargnoli, M. C., Peris, K. & Landi, M. T. Comprehensive evaluation of allele frequency differences of MC1R variants across populations. Hum. Mutat. 28, 495–505 (2007).

    Article  CAS  PubMed  Google Scholar 

  59. Palmer, J. S. et al. Melanocortin-1 receptor polymorphisms and risk of melanoma: is the association explained solely by pigmentation phenotype? Am. J. Hum. Genet. 66, 176–186 (2000).

    Article  CAS  PubMed  Google Scholar 

  60. Kennedy, C. et al. Melanocortin 1 receptor (MC1R) gene variants are associated with an increased risk for cutaneous melanoma which is largely independent of skin type and hair color. J. Invest. Dermatol. 117, 294–300 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Slominski, A., Paus, R. & Wortsman, J. Can some melanotropins modulate keratinocyte proliferation? J. Invest. Dermatol. 97, 747 (1991).

    Article  CAS  PubMed  Google Scholar 

  62. Wintzen, M., Yaar, M., Burbach, J. P. & Gilchrest, B. A. Proopiomelanocortin gene product regulation in keratinocytes. J. Invest. Dermatol. 106, 673–678 (1996).

    Article  CAS  PubMed  Google Scholar 

  63. Corre, S. et al. UV-induced expression of key component of the tanning process, the POMC and MC1R genes, is dependent on the p-38-activated upstream stimulating factor-1 (USF-1). J. Biol. Chem. 279, 51226–51233 (2004).

    Article  CAS  PubMed  Google Scholar 

  64. Cui, R. et al. Central role of p53 in the suntan response and pathologic hyperpigmentation. Cell 128, 853–864 (2007).

    Article  CAS  PubMed  Google Scholar 

  65. Gudbjartsson, D. F. et al. ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma. Nature Genet. 40, 886–891 (2008). This is a recent large-scale survey of genetic variants predisposing to BCC carcinogenesis.

    Article  CAS  PubMed  Google Scholar 

  66. Kraemer, K. H., Lee, M. M., Andrews, A. D. & Lambert, W. C. The role of sunlight and DNA repair in melanoma and nonmelanoma skin cancer. Arch. Dermatol. 130, 1018–1021 (1994).

    Article  CAS  PubMed  Google Scholar 

  67. Berwick, M. & Vineis, P. Markers of DNA repair and susceptibility to cancer in humans: an epidemiologic review. J. Natl Cancer Inst. 92, 874–897 (2000).

    Article  CAS  PubMed  Google Scholar 

  68. Wei, Q., Matanoski, G. M., Farmer, E. R., Hedayati, M. A. & Grossman, L. DNA repair capacity for ultraviolet light-induced damage is reduced in peripheral lymphocytes from patients with basal cell carcinoma. J. Invest. Dermatol. 104, 933–936 (1995).

    Article  CAS  PubMed  Google Scholar 

  69. Dybdahl, M., Frentz, G., Vogel, U., Wallin, H. & Nexo, B. A. Low DNA repair is a risk factor in skin carcinogenesis: a study of basal cell carcinoma in psoriasis patients. Mutat. Res. 433, 15–22 (1999).

    Article  CAS  PubMed  Google Scholar 

  70. Segerback, D., Strozyk, M., Snellman, E., & Hemminki, K. Repair of UV dimers in skin DNA of patients with basal cell carcinoma. Cancer Epidemiol. Biomarkers Prev. 17, 2388–2392 (2008).

    Article  PubMed  Google Scholar 

  71. Han, S. et al. DNA repair gene XRCC3 polymorphisms and cancer risk: a meta-analysis of 48 case-control studies. Eur. J. Hum. Genet. 14, 1136–1144 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Han, J., Colditz, G. A., Samson, L. D. & Hunter, D. J. Polymorphisms in DNA double-strand break repair genes and skin cancer risk. Cancer Res. 64, 3009–3013 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Thirumaran, R. K. et al. Single nucleotide polymorphisms in DNA repair genes and basal cell carcinoma of skin. Carcinogenesis 27, 1676–1681 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. Jacobsen, N. R. et al. No association between the DNA repair gene XRCC3 T241M polymorphism and risk of skin cancer and breast cancer. Cancer Epidemiol. Biomarkers Prev. 12, 584–585 (2003).

    CAS  PubMed  Google Scholar 

  75. Festa, F. et al. Basal cell carcinoma and variants in genes coding for immune response, DNA repair, folate and iron metabolism. Mutat. Res. 574, 105–111 (2005).

    Article  CAS  PubMed  Google Scholar 

  76. Chen, Y. C. et al. Genetic polymorphism in p53 codon 72 and skin cancer in southwestern Taiwan. J. Environ. Sci. Health A Tox Hazard Subst. Environ. Eng. 38, 201–211 (2003).

    Article  PubMed  CAS  Google Scholar 

  77. Han, J., Cox, D. G., Colditz, G. A. & Hunter, D. J. The p53 codon 72 polymorphism, sunburns, and risk of skin cancer in US Caucasian women. Mol. Carcinog. 45, 694–700 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. Stefanaki, I. et al. p53 codon 72 Pro homozygosity increases the risk of cutaneous melanoma in individuals with dark skin complexion and among noncarriers of melanocortin 1 receptor red hair variants. Br. J. Dermatol. 156, 357–362 (2007).

    Article  CAS  PubMed  Google Scholar 

  79. McGregor, J. M. et al. Relationship between p53 codon 72 polymorphism and susceptibility to sunburn and skin cancer. J. Invest. Dermatol. 119, 84–90 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Wilkening, S. et al. No association between MDM2 SNP309 promoter polymorphism and basal cell carcinoma of the skin. Br. J. Dermatol. 157, 375–377 (2007).

    Article  CAS  PubMed  Google Scholar 

  81. Asplund, A. et al. PTCH codon 1315 polymorphism and risk for nonmelanoma skin cancer. Br. J. Dermatol. 152, 868–873 (2005).

    Article  CAS  PubMed  Google Scholar 

  82. Wakabayashi, Y., Mao, J. H., Brown, K., Girardi, M. & Balmain, A. Promotion of Hras-induced squamous carcinomas by a polymorphic variant of the Patched gene in FVB mice. Nature 445, 761–765 (2007).

    Article  CAS  PubMed  Google Scholar 

  83. Yoon, J. W. et al. Gene expression profiling leads to identification of GLI1-binding elements in target genes and a role for multiple downstream pathways in GLI1-induced cell transformation. J. Biol. Chem. 277, 5548–5555 (2002).

    Article  CAS  PubMed  Google Scholar 

  84. Howell, B. G. et al. Microarray profiles of human basal cell carcinoma: insights into tumor growth and behavior. J. Dermatol. Sci. 39, 39–51 (2005).

    Article  CAS  PubMed  Google Scholar 

  85. O'Driscoll, L. et al. Investigation of the molecular profile of basal cell carcinoma using whole genome microarrays. Mol. Cancer 5, 74 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Yu, M. et al. Superficial, nodular, and morpheiform basal-cell carcinomas exhibit distinct gene expression profiles. J. Invest. Dermatol. 128, 1797–1805 (2008).

    Article  CAS  PubMed  Google Scholar 

  87. Asplund, A. et al. Expression profiling of microdissected cell populations selected from basal cells in normal epidermis and basal cell carcinoma. Br. J. Dermatol. 158, 527–538 (2008).

    Article  CAS  PubMed  Google Scholar 

  88. Xie, J. et al. A role of PDGFRα in basal cell carcinoma proliferation. Proc. Natl Acad. Sci. USA 98, 9255–9259 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Bigelow, R. L. et al. Transcriptional regulation of bcl-2 mediated by the sonic hedgehog signaling pathway through gli-1. J. Biol. Chem. 279, 1197–1205 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Regl, G. et al. Activation of the BCL2 promoter in response to Hedgehog/GLI signal transduction is predominantly mediated by GLI2. Cancer Res. 64, 7724–7731 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Kump, E., Ji, J., Wernli, M., Hausermann, P. & Erb, P. Gli2 upregulates cFlip and renders basal cell carcinoma cells resistant to death ligand-mediated apoptosis. Oncogene 27, 3856–3864 (2008).

    Article  CAS  PubMed  Google Scholar 

  92. Li, C. et al. IFNα induces Fas expression and apoptosis in hedgehog pathway activated BCC cells through inhibiting Ras–Erk signaling. Oncogene 23, 1608–1617 (2004).

    Article  CAS  PubMed  Google Scholar 

  93. Athar, M. et al. Inhibition of smoothened signaling prevents ultraviolet B-induced basal cell carcinomas through regulation of Fas expression and apoptosis. Cancer Res. 64, 7545–7552 (2004).

    Article  CAS  PubMed  Google Scholar 

  94. Leung, C. et al. Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas. Nature 428, 337–341 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Reinisch, C. M., Uthman, A., Erovic, B. M. & Pammer, J. Expression of BMI-1 in normal skin and inflammatory and neoplastic skin lesions. J. Cutan. Pathol. 34, 174–180 (2007).

    Article  PubMed  Google Scholar 

  96. Kenney, A. M. & Rowitch, D. H. Sonic hedgehog promotes G1 cyclin expression and sustained cell cycle progression in mammalian neuronal precursors. Mol. Cell. Biol. 20, 9055–9067 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Rao, G. et al. Sonic hedgehog and insulin-like growth factor signaling synergize to induce medulloblastoma formation from nestin-expressing neural progenitors in mice. Oncogene 23, 6156–6162 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Hahn, H. et al. Patched target Igf2 is indispensable for the formation of medulloblastoma and rhabdomyosarcoma. J. Biol. Chem. 15, 28341–28344 (2000).

    Article  Google Scholar 

  99. Levitt, R. J., Zhao, Y., Blouin, M. J. & Pollak, M. The hedgehog pathway inhibitor cyclopamine increases levels of p27, and decreases both expression of IGF-II and activation of Akt in PC-3 prostate cancer cells. Cancer Lett. 255, 300–306 (2007).

    Article  CAS  PubMed  Google Scholar 

  100. Lipinski, R. J. et al. Sonic hedgehog signaling regulates the expression of insulin-like growth factor binding protein-6 during fetal prostate development. Dev. Dyn. 233, 829–836 (2005).

    Article  CAS  PubMed  Google Scholar 

  101. Allan, G. J. et al. Major components of the insulin-like growth factor axis are expressed early in chicken embryogenesis, with IGF binding protein (IGFBP)-5 expression subject to regulation by sonic hedgehog. Anat. Embryol. (Berl.) 207, 73–84 (2003).

    Article  CAS  Google Scholar 

  102. Elia, D., Madhala, D., Ardon, E., Reshef, R. & Halevy, O. Sonic hedgehog promotes proliferation and differentiation of adult muscle cells: involvement of MAPK/ERK and PI3K/Akt pathways. Biochim. Biophys. Acta 1773, 1438–1446 (2007).

    Article  CAS  PubMed  Google Scholar 

  103. Riobo, N. A., Lu, K., Ai, X., Haines, G. M. & Emerson, C. P., Jr. Phosphoinositide 3-kinase and Akt are essential for sonic hedgehog signaling. Proc. Natl Acad. Sci. USA 103, 4505–4510 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Teh, M. T. et al. FOXM1 is a downstream target of Gli1 in basal cell carcinomas. Cancer Res. 62, 4773–4780 (2002).

    CAS  PubMed  Google Scholar 

  105. Yoshida, Y., Wang, I. C., Yoder, H. M., Davidson, N. O. & Costa, R. H. The forkhead box M1 transcription factor contributes to the development and growth of mouse colorectal cancer. Gastroenterology 132, 1420–1431 (2007).

    Article  CAS  PubMed  Google Scholar 

  106. Dai, B. et al. Aberrant FoxM1B expression increases matrix metalloproteinase-2 transcription and enhances the invasion of glioma cells. Oncogene 26, 6212–6219 (2007).

    Article  CAS  PubMed  Google Scholar 

  107. Liu, M. et al. FoxM1B is overexpressed in human glioblastomas and critically regulates the tumorigenicity of glioma cells. Cancer Res. 66, 3593–3602 (2006).

    Article  CAS  PubMed  Google Scholar 

  108. Kalin, T. V. et al. Increased levels of the FoxM1 transcription factor accelerate development and progression of prostate carcinomas in both TRAMP and LADY transgenic mice. Cancer Res. 66, 1712–1720 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Kim, I. M. et al. The forkhead box m1 transcription factor stimulates the proliferation of tumor cells during development of lung cancer. Cancer Res. 66, 2153–2161 (2006).

    Article  CAS  PubMed  Google Scholar 

  110. Tan, Y., Raychaudhuri, P. & Costa, R. H. Chk2 mediates stabilization of the FoxM1 transcription factor to stimulate expression of DNA repair genes. Mol. Cell. Biol. 27, 1007–1016 (2007).

    Article  CAS  PubMed  Google Scholar 

  111. Schuller, U. et al. Forkhead transcription factor FoxM1 regulates mitotic entry and prevents spindle defects in cerebellar granule neuron precursors. Mol. Cell. Biol. 27, 8259–8270 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Wonsey, D. R. & Follettie, M. T. Loss of the forkhead transcription factor FoxM1 causes centrosome amplification and mitotic catastrophe. Cancer Res. 65, 5181–5189 (2005).

    Article  CAS  PubMed  Google Scholar 

  113. Kalinichenko, V. V. et al. Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor. Genes Dev. 18, 830–850 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Gusarova, G. A. et al. A cell-penetrating ARF peptide inhibitor of FoxM1 in mouse hepatocellular carcinoma treatment. J. Clin. Invest. 117, 99–111 (2007).

    Article  CAS  PubMed  Google Scholar 

  115. Radhakrishnan, S. K. et al. Identification of a chemical inhibitor of the oncogenic transcription factor forkhead box M1. Cancer Res. 66, 9731–9735 (2006).

    Article  CAS  PubMed  Google Scholar 

  116. Eichberger, T. et al. FOXE1, a new transcriptional target of GLI2, is expressed in human epidermis and basal cell carcinoma. J. Invest. Dermatol. 122, 1180–1187 (2004).

    Article  CAS  PubMed  Google Scholar 

  117. Brancaccio, A. et al. Requirement of the forkhead gene Foxe1, a target of sonic hedgehog signaling, in hair follicle morphogenesis. Hum. Mol. Genet. 13, 2595–2606 (2004).

    Article  CAS  PubMed  Google Scholar 

  118. Yang, S. H. et al. Pathological responses to oncogenic Hedgehog signaling in skin are dependent on canonical Wnt/β-catenin signaling. Nature Genet. 40, 1130–1135 (2008).

    Article  CAS  PubMed  Google Scholar 

  119. Nilsson, M. et al. Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1. Proc. Natl Acad. Sci. USA 97, 3438–3443 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Grachtchouk, M. et al. Basal cell carcinomas in mice overexpressing Gli2 in skin. Nature Genet. 24, 216–217 (2000).

    Article  CAS  PubMed  Google Scholar 

  121. Aszterbaum, M. et al. Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in patched heterozygous knockout mice. Nature Med. 5, 1285–1291 (1999).

    Article  CAS  PubMed  Google Scholar 

  122. Svard, J. et al. Genetic elimination of Suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway. Dev. Cell 10, 187–197 (2006).

    Article  PubMed  CAS  Google Scholar 

  123. Grachtchouk, V. et al. The magnitude of hedgehog signaling activity defines skin tumor phenotype. EMBO J. 22, 2741–2751 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Wetmore, C., Eberhart, D. E. & Curran, T. Loss of p53 but not ARF accelerates medulloblastoma in mice heterozygous for patched. Cancer Res. 61, 513–516 (2001).

    CAS  PubMed  Google Scholar 

  125. Hadley, M. E. & Dorr, R. T. Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization. Peptides 27, 921–930 (2006).

    Article  CAS  PubMed  Google Scholar 

  126. Gange, R. W., Blackett, A. D., Matzinger, E. A., Sutherland, B. M. & Kochevar, I. E. Comparative protection efficiency of UVA- and UVB-induced tans against erythema and formation of endonuclease-sensitive sites in DNA by UVB in human skin. J. Invest. Dermatol. 85, 362–364 (1985).

    Article  CAS  PubMed  Google Scholar 

  127. Eller, M. S., Asarch, A. & Gilchrest, B. A. Photoprotection in human skin — a multifaceted SOS response. Photochem. Photobiol. 84, 339–349 (2008).

    Article  CAS  PubMed  Google Scholar 

  128. Arad, S. et al. Topical thymidine dinucleotide treatment reduces development of ultraviolet-induced basal cell carcinoma in Ptch-1+/− mice. Am. J. Pathol. 172, 1248–1255 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Yarosh, D. B. & Klein, J. DNA repair enzymes in prevention of photocarcinogenesis. Photochem. Photobiol. 63, 445–447 (1996).

    Article  CAS  PubMed  Google Scholar 

  130. Yarosh, D. et al. Effect of topically applied T4 endonuclease V in liposomes on skin cancer in xeroderma pigmentosum: a randomised study. Xeroderma Pigmentosum Study Group. Lancet 357, 926–929 (2001).

    Article  CAS  PubMed  Google Scholar 

  131. Peck, G. L. et al. Treatment and prevention of basal cell carcinoma with oral isotretinoin. J. Am. Acad. Dermatol. 19, 176–185 (1988).

    Article  CAS  PubMed  Google Scholar 

  132. Goldberg, L. H., Hsu, S. H. & Alcalay, J. Effectiveness of isotretinoin in preventing the appearance of basal cell carcinomas in basal cell nevus syndrome. J. Am. Acad. Dermatol. 21, 144–145 (1989).

    Article  CAS  PubMed  Google Scholar 

  133. Kraemer, K. H., DiGiovanna, J. J., Moshell, A. N., Tarone, R. E. & Peck, G. L. Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin. N. Engl. J. Med. 318, 1633–1637 (1988).

    Article  CAS  PubMed  Google Scholar 

  134. Tangrea, J. A. et al. Long-term therapy with low-dose isotretinoin for prevention of basal cell carcinoma: a multicenter clinical trial. J. Natl Cancer Inst. 84, 328–332 (1992).

    Article  CAS  PubMed  Google Scholar 

  135. Levine, N. et al. Trial of retinol and isotretinoin in skin cancer prevention: a randomized double-blind, controlled trial. Cancer Epidemiol. Biomarkers Prevention 6, 957–961 (1997).

    CAS  Google Scholar 

  136. Peris, K., Fargnoli, M. C. & Chimenti, S. Preliminary observations on the use of topical tazarotene to treat basal-cell carcinoma. N. Engl. J. Med. 341, 1767–1768 (1999).

    Article  CAS  PubMed  Google Scholar 

  137. Duvic, M. et al. Tazarotene-induced gene 3 is suppressed in basal cell carcinomas and reversed in vivo by tazarotene application. J. Invest. Dermatol. 121, 902–909 (2003).

    Article  CAS  PubMed  Google Scholar 

  138. Bianchi, L. et al. Topical treatment of basal cell carcinoma with tazarotene: a clinicopathological study on a large series of cases. Br. J. Dermatol. 151, 148–156 (2004).

    Article  CAS  PubMed  Google Scholar 

  139. So, P. L. et al. Topical tazarotene chemoprevention reduces basal cell carcinoma number and size in Ptch1+/− mice exposed to ultraviolet or ionizing radiation. Cancer Res. 64, 4385–4389 (2004).

    Article  CAS  PubMed  Google Scholar 

  140. So, P. L., Fujimoto, M. A. & Epstein, E. H. Jr. Pharmacologic retinoid signaling and physiologic retinoic acid receptor signaling inhibit basal cell carcinoma tumorigenesis. Mol. Cancer Ther. 7, 1275–1284 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Black, H. S. et al. Evidence that a low-fat diet reduces the occurence of non-melanoma skin cancer. Int. J. Cancer 62, 165–169 (1995).

    Article  CAS  PubMed  Google Scholar 

  142. Carneiro, B. A., Watkin, W. G., Mehta, U. K. & Brockstein, B. E. Metastatic basal cell carcinoma: complete response to chemotherapy and associated pure red cell aplasia. Cancer Invest. 24, 396–400 (2006).

    Article  PubMed  Google Scholar 

  143. Binns, W., James, L. F., Shupe, J. L. & Everett, G. A congenital cyclopian-type malformation in lambs induced by maternal ingestion of a range plant, Veratrum californicum. Am. J. Vet. Res. 24, 1164–1175 (1963).

    CAS  PubMed  Google Scholar 

  144. Tabs, S. & Avci, O. Induction of the differentiation and apoptosis of tumor cells in vivo with efficiency and selectivity. Eur. J. Dermatol. 14, 96–102 (2004).

    PubMed  Google Scholar 

  145. Cooper, M. K., Porter, J. A., Young, K. E. & Beachy, P. A. Teratogen-mediated inhibition of target tissue response to Shh signaling. Science 280, 1603–1607 (1998).

    Article  CAS  PubMed  Google Scholar 

  146. Incardona, J. P., Gaffield, W., Kapur, R. P. & Roelink, H. The teratogenic Veratrum alkaloid cyclopamine inhibits sonic hedgehog signal transduction. Development 125, 3553–3562 (1998).

    CAS  PubMed  Google Scholar 

  147. Chen, J. K., Taipale, J., Cooper, M. K. & Beachy, P. A. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev. 16, 2743–2748 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Taipale, J. et al. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 406, 1005–1009 (2000).

    Article  CAS  PubMed  Google Scholar 

  149. Van Hoff, D. D. et al. Efficacy data of GDC-0449, a systemic Hedgehog (Hh) pathway antagonist, in a first-in-human, first-in-class, phase I study with locally advanced, multifocal or metastatic basal cell carcinoma patients. Proc. 99th Annu. Meeting Am. Assoc. Cancer Res. abstract LB-138 (2008).

  150. Palma, V. et al. Sonic hedgehog controls stem cell behavior in the postnatal and adult brain. Development 132, 335–344 (2005).

    Article  CAS  PubMed  Google Scholar 

  151. Balordi, F. & Fishell, G. Mosaic removal of hedgehog signaling in the adult SVZ reveals that the residual wild-type stem cells have a limited capacity for self-renewal. J. Neurosci. 27, 14248–14259 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Zhang, C. L., Zou, Y., He, W., Gage, F. H. & Evans, R. M. A role for adult TLX-positive neural stem cells in learning and behaviour. Nature 451, 1004–1007 (2008).

    Article  CAS  PubMed  Google Scholar 

  153. Paladini, R. D., Saleh, J., Qian, C., Xu, G. X. & Rubin, L. L. Modulation of hair growth with small molecule agonists of the hedgehog signaling pathway. J. Invest. Dermatol. 125, 638–646 (2005).

    Article  CAS  PubMed  Google Scholar 

  154. Miura, H., Kusakabe, Y. & Harada, S. Cell lineage and differentiation in taste buds. Arch. Histol. Cytol. 69, 209–225 (2006).

    Article  CAS  PubMed  Google Scholar 

  155. Angot, E. et al. Chemoattractive activity of sonic hedgehog in the adult subventricular zone modulates the number of neural precursors reaching the olfactory bulb. Stem Cells 10 Jul 2008 [epub ahead of print].

  156. Kimura, H., Ng, J. M. & Curran, T. Transient inhibition of the Hedgehog pathway in young mice causes permanent defects in bone structure. Cancer Cell 13, 249–260 (2008).

    Article  CAS  PubMed  Google Scholar 

  157. Arad, S., Konnikov, N., Goukassian, D. A. & Gilchrest, B. A. Quantification of inducible SOS-like photoprotective responses in human skin. J. Invest. Dermatol. 127, 2629–2636 (2007).

    Article  CAS  PubMed  Google Scholar 

  158. Bijlsma, M. F. et al. Repression of smoothened by patched-dependent (pro-)vitamin D3 secretion. PLoS Biol. 4, e232 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  159. Holick, M. F. et al. Photosynthesis of previtamin D3 in human skin and the physiologic consequences. Science 210, 203–205 (1980).

    Article  CAS  PubMed  Google Scholar 

  160. MacLaughlin, J. & Holick, M. F. Aging decreases the capacity of human skin to produce vitamin D3. J. Clin. Invest. 76, 1536–1538 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Vogt, A., Hebert, J., Hwang, J., Lu, Y. & Epstein, E. H. Anti-rejection drug treatment increases basal cell carcinoma burden in Ptch1+/− mice. J. Invest. Dermatol. 124, 263–267 (2005).

    Article  CAS  PubMed  Google Scholar 

  162. Karhadkar, S. S. et al. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 431, 707–712 (2004).

    Article  CAS  PubMed  Google Scholar 

  163. Van Scott, E. J. & Reinertson, R. P. The modulating influence of stromal environment on epithelial cells studies in human autoransplants. J. Invest. Dermatol. 36, 109–131 (1961).

    Article  CAS  PubMed  Google Scholar 

  164. Williams, T. et al. The oncogenic GLI (GLI1 and GLI2) transcription factors induce characteristics of cellular senescence in N/Tert-1 keratinocytes. J. Invest. Dermatol. 127, s92 (2007).

    Article  CAS  Google Scholar 

  165. Gorlin, R. J. Nevoid basal-cell carcinoma syndrome. Medicine (Baltimore) 66, 98–113 (1987).

    Article  CAS  Google Scholar 

  166. Evans, D. G. R., Farndon, P. A., Burnell, L. D., Gattamaneni, H. R. & Birch, J. M. The incidence of Gorlin syndrome in 173 consecutive cases of medulloblastoma. Br. J. Cancer 64, 959–961 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Johnson, A. D., Hebert, A. A. & Esterly, N. B. Nevoid basal cell carcinoma syndrome: bilateral ovarian fibromas in a 3 1/2-year-old girl. J. Am. Acad. Dermatol. 14, 371–374 (1986). References 165–167 review the clinical aspects of BCNS.

    Article  CAS  PubMed  Google Scholar 

  168. Kimonis, V. E. et al. Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. Am. J. Med. Genet. 69, 299–308 (1997).

    Article  CAS  PubMed  Google Scholar 

  169. Miller, K. L. et al. XPA, haplotypes, and risk of basal and squamous cell carcinoma. Carcinogenesis 27, 1670–1675 (2006).

    Article  CAS  PubMed  Google Scholar 

  170. Kang, S. Y. et al. Polymorphisms in the DNA repair gene XRCC1 associated with basal cell carcinoma and squamous cell carcinoma of the skin in a Korean population. Cancer Sci. 98, 716–720 (2007).

    Article  CAS  PubMed  Google Scholar 

  171. Han, J., Hankinson, S. E., Colditz, G. A. & Hunter, D. J. Genetic variation in XRCC1, sun exposure, and risk of skin cancer. Br. J. Cancer 91, 1604–1609 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Dybdahl, M., Vogel, U., Frentz, G., Wallin, H. & Nexo, B. A. Polymorphisms in the DNA repair gene XPD: correlations with risk and age at onset of basal cell carcinoma. Cancer Epidemiol. Biomarkers Prev. 8, 77–81 (1999).

    CAS  PubMed  Google Scholar 

  173. Lovatt, T. et al. Polymorphism in the nuclear excision repair gene ERCC2/XPD: association between an exon 6–exon 10 haplotype and susceptibility to cutaneous basal cell carcinoma. Hum. Mutat. 25, 353–359 (2005).

    Article  CAS  PubMed  Google Scholar 

  174. Vogel, U. et al. Effect of polymorphisms in XPD, RAI, ASE-1 and ERCC1 on the risk of basal cell carcinoma among Caucasians after age 50. Cancer Detect. Prev. 29, 209–214 (2005).

    Article  CAS  PubMed  Google Scholar 

  175. Han, J., Colditz, G. A. & Hunter, D. J. Lack of associations of selected variants in genes involved in cell cycle and apoptosis with skin cancer risk. Cancer Epidemiol. Biomarkers Prev. 15, 592–593 (2006).

    Article  PubMed  Google Scholar 

  176. Lin, Q. et al. Increased susceptibility to UV-induced skin carcinogenesis in polymerase eta-deficient mice. Cancer Res. 66, 87–94 (2006).

    Article  CAS  PubMed  Google Scholar 

  177. Meeran, S. M., Mantena, S. K., Meleth, S., Elmets, C. A. & Katiyar, S. K. Interleukin-12-deficient mice are at greater risk of UV radiation-induced skin tumors and malignant transformation of papillomas to carcinomas. Mol. Cancer Ther. 5, 825–832 (2006).

    Article  CAS  PubMed  Google Scholar 

  178. Schwarz, T. Photoimmunosuppression. Photodermatol. Photoimmunol. Photomed. 18, 141–145 (2002).

    Article  CAS  PubMed  Google Scholar 

  179. Reynolds, N. J., Todd, C. & Angus, B. Overexpression of protein kinase C-α and -β isozymes by stromal dendritic cells in basal and squamous cell carcinoma. Br. J. Dermatol. 136, 666–673 (1997).

    Article  CAS  PubMed  Google Scholar 

  180. Neill, G. W. et al. Loss of protein kinase Cα expression may enhance the tumorigenic potential of Gli1 in basal cell carcinoma. Cancer Res. 63, 4692–4697 (2003).

    CAS  PubMed  Google Scholar 

  181. Riobo, N. A., Haines, G. M. & Emerson, C. P. Jr. Protein kinase C-δ and mitogen-activated protein/extracellular signal-regulated kinase-1 control GLI activation in hedgehog signaling. Cancer Res. 66, 839–845 (2006).

    Article  CAS  PubMed  Google Scholar 

  182. Lauth, M., Bergstrom, A. & Toftgard, R. Phorbol esters inhibit the Hedgehog signalling pathway downstream of Suppressor of Fused, but upstream of Gli. Oncogene 26, 5163–5168 (2007).

    Article  CAS  PubMed  Google Scholar 

  183. Tang, X. et al. Ornithine decarboxylase is a target for chemoprevention of basal and squamous cell carcinomas in Ptch1+/− mice. J. Clin. Invest. 113, 867–875 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Thyberg, J. & Fredholm, B. B. Induction of ornithine decarboxylase activity and putrescine synthesis in arterial smooth muscle cells stimulated with platelet-derived growth factor. Exp. Cell Res. 170, 160–169 (1987).

    Article  CAS  PubMed  Google Scholar 

  185. Kasper, M. et al. Selective modulation of Hedgehog/GLI target gene expression by epidermal growth factor signaling in human keratinocytes. Mol. Cell. Biol. 26, 6283–6298 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Mimeault, M. et al. Combined targeting of epidermal growth factor receptor and hedgehog signaling by gefitinib and cyclopamine cooperatively improves the cytotoxic effects of docetaxel on metastatic prostate cancer cells. Mol. Cancer Ther. 6, 967–978 (2007).

    Article  CAS  PubMed  Google Scholar 

  187. Ikeuchi, T., Urano, Y., Fukuhara, K., Nakanishi, H. & Arase, S. Light microscopic autoradiographical analysis of [125I]epidermal growth factor binding in basal cell epithelioma and squamous cell carcinoma of the skin. J. Dermatol. 20, 219–225 (1993).

    Article  CAS  PubMed  Google Scholar 

  188. Mimeault, M. et al. Cytotoxic effects induced by a combination of cyclopamine and gefitinib, the selective hedgehog and epidermal growth factor receptor signaling inhibitors, in prostate cancer cells. Int. J. Cancer 118, 1022–1031 (2006).

    Article  CAS  PubMed  Google Scholar 

  189. Hu, W. G., Liu, T., Xiong, J. X. & Wang, C. Y. Blockade of sonic hedgehog signal pathway enhances antiproliferative effect of EGFR inhibitor in pancreatic cancer cells. Acta Pharmacol. Sin. 28, 1224–1230 (2007).

    Article  CAS  PubMed  Google Scholar 

  190. Neill, G. W. et al. GLI1 repression of ERK activity correlates with colony formation and impaired migration in human epidermal keratinocytes. Carcinogenesis 29, 738–746 (2008).

    Article  CAS  PubMed  Google Scholar 

  191. Dennler, S. et al. Induction of sonic hedgehog mediators by transforming growth factor-β: Smad3-dependent activation of Gli2 and Gli1 expression in vitro and in vivo. Cancer Res. 67, 6981–6986 (2007).

    Article  CAS  PubMed  Google Scholar 

  192. Stamp, G. W. et al. Transforming growth factor-β distribution in basal cell carcinomas: relationship to proliferation index. Br. J. Dermatol. 129, 57–64 (1993).

    Article  CAS  PubMed  Google Scholar 

  193. Gambichler, T. et al. Increased expression of TGF-β/Smad proteins in basal cell carcinoma. Eur. J. Med. Res. 12, 509–514 (2007).

    CAS  PubMed  Google Scholar 

  194. Verhaegh, M. E., Arends, J. W., Majoie, I. M., Hoekzema, R. & Neumann, H. A. Transforming growth factor-β and bcl-2 distribution patterns distinguish trichoepithelioma from basal cell carcinoma. Dermatol. Surg. 23, 695–700 (1997).

    CAS  PubMed  Google Scholar 

  195. Lange, D. et al. Expression of TGF-β related Smad proteins in human epithelial skin tumors. Int. J. Oncol. 14, 1049–1056 (1999).

    CAS  PubMed  Google Scholar 

  196. Sneddon, J. B. et al. Bone morphogenetic protein antagonist gremlin 1 is widely expressed by cancer-associated stromal cells and can promote tumor cell proliferation. Proc. Natl Acad. Sci. USA 103, 14842–14847 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Thelu, J., Rossio, P. & Favier, B. Notch signalling is linked to epidermal cell differentiation level in basal cell carcinoma, psoriasis and wound healing. BMC Dermatol. 2, 7 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  198. Nicolas, M. et al. Notch1 functions as a tumor suppressor in mouse skin. Nature Genet. 33, 416–421 (2003).

    Article  CAS  PubMed  Google Scholar 

  199. Christenson, L. J. et al. Incidence of basal cell and squamous cell carcinomas in a population younger than 40 years. JAMA 294, 681–690 (2005).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Original research of Ervin H. Epstein is supported by grants from the National Institutes of Health (CA109584, CA115992, AR050440) as well as generous support from the Michael J. Rainen Family Foundation.

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

E.H.E has received consulting fees from AGI, Bristol–Myers Squibb, Guris, Exelexis, Genentech, Infinity and Merck.

Related links

Related links

DATABASES

National Cancer Institute

alopecia

BCC

breast cancer

colorectal

dysgeusia

glioblastoma

medulloblastomas

melanoma

NMSC

ovarian

rhabdomyosarcomas

SCC

single nucleotide polymorphisms

National Cancer Institute Drug Dictionary 

carboplatin

celecoxib

imatinib

p aclitaxel

sorafenib

tazarotene

OMIM

basal-cell nevus syndrome

xeroderma pigmentosum

FURTHER INFORMATION

Curis website 2006 press release

Oral History of Human Genetics Project Interview with Robert Gorlin

Glossary

Medicare

The US federal government medical insurance programme that covers all citizens over the age of 65.

Linkage disequilibrium

When alleles at two or more genetic loci occur more frequently in the population than expected given the known allele frequencies and recombination fraction between the two loci. This indicates that the loci are tightly linked; that is, sufficiently close together on the same chromosome to be co-inherited more than 50% of the time.

Parenteral

Administration of a drug by injection, such as subcutaneous, intramuscular or intravenous, rather than administration through the alimentary canal.

Cyclopamine

The teratogenic component of corn lilies that is responsible for the cyclopean (one-eyed) phenotype of lambs born of dams eating this plant.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Epstein, E. Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer 8, 743–754 (2008). https://doi.org/10.1038/nrc2503

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc2503

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing