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. 1989 May;81:23–27. doi: 10.1289/ehp.898123

Chemical induction of oncogene mutations and growth factor activity in mouse skin carcinogenesis.

B Bailleul 1, K Brown 1, M Ramsden 1, R J Akhurst 1, F Fee 1, A Balmain 1
PMCID: PMC1567527  PMID: 2667981

Abstract

The goal of understanding the molecular basis of human tumor development has been greatly facilitated by the use of animal model systems in which the etiology of tumor development can be carefully controlled. Environmental chemicals, either naturally occurring or artificially produced, are thought to make a major contribution to the human tumor burden. Many of the concepts of multistage carcinogenesis have been developed and refined using the mouse skin model system and the work described in this article has been carried out in an attempt to analyze the molecular changes that are associated with the initiation of tumor development, the selection of initiated cells to form papillomas, or the progression of premalignant tumors to carcinoma. We have analyzed a number of skin tumors induced in mice by a two-stage initiation and promotion protocol and have detected a high frequency of c-ras oncogene mutations in this system. The mutation found in each case correlates well with the known reactivity of the carcinogens used. It has also been shown that where ras activation occurs this represents an early event in the tumor model system. Transforming growth factor beta is induced in mouse skin by tumor promoter treatment and may therefore play a role in the selection of initiated cells to form papillomas. Additional events, some of which involve the loss of normal ras alleles and possibly tumor suppressor genes, appear to take place at a later stage of carcinogenesis.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akhurst R. J., Fee F., Balmain A. Localized production of TGF-beta mRNA in tumour promoter-stimulated mouse epidermis. Nature. 1988 Jan 28;331(6154):363–365. doi: 10.1038/331363a0. [DOI] [PubMed] [Google Scholar]
  2. Alitalo K., Schwab M. Oncogene amplification in tumor cells. Adv Cancer Res. 1986;47:235–281. doi: 10.1016/s0065-230x(08)60201-8. [DOI] [PubMed] [Google Scholar]
  3. Bailleul B., Galiègue S., Loucheux-Lefebvre M. H. Adducts from the reaction of O,O'-diacetyl or O-acetyl derivatives of the carcinogen 4-hydroxyaminoquinoline 1-oxide with purine nucleosides. Cancer Res. 1981 Nov;41(11 Pt 1):4559–4565. [PubMed] [Google Scholar]
  4. Balmain A., Pragnell I. B. Mouse skin carcinomas induced in vivo by chemical carcinogens have a transforming Harvey-ras oncogene. Nature. 1983 May 5;303(5912):72–74. doi: 10.1038/303072a0. [DOI] [PubMed] [Google Scholar]
  5. Balmain A., Ramsden M., Bowden G. T., Smith J. Activation of the mouse cellular Harvey-ras gene in chemically induced benign skin papillomas. Nature. 1984 Feb 16;307(5952):658–660. doi: 10.1038/307658a0. [DOI] [PubMed] [Google Scholar]
  6. Barbacid M. ras genes. Annu Rev Biochem. 1987;56:779–827. doi: 10.1146/annurev.bi.56.070187.004023. [DOI] [PubMed] [Google Scholar]
  7. Bishop J. M. Cellular oncogenes and retroviruses. Annu Rev Biochem. 1983;52:301–354. doi: 10.1146/annurev.bi.52.070183.001505. [DOI] [PubMed] [Google Scholar]
  8. Bos J. L. The ras gene family and human carcinogenesis. Mutat Res. 1988 May;195(3):255–271. doi: 10.1016/0165-1110(88)90004-8. [DOI] [PubMed] [Google Scholar]
  9. Capon D. J., Chen E. Y., Levinson A. D., Seeburg P. H., Goeddel D. V. Complete nucleotide sequences of the T24 human bladder carcinoma oncogene and its normal homologue. Nature. 1983 Mar 3;302(5903):33–37. doi: 10.1038/302033a0. [DOI] [PubMed] [Google Scholar]
  10. Castagna M., Takai Y., Kaibuchi K., Sano K., Kikkawa U., Nishizuka Y. Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters. J Biol Chem. 1982 Jul 10;257(13):7847–7851. [PubMed] [Google Scholar]
  11. Damante G., Filetti S., Rapoport B. Nucleotide sequence and characterization of the 5' flanking region of the rat Ha-ras protooncogene. Proc Natl Acad Sci U S A. 1987 Feb;84(3):774–778. doi: 10.1073/pnas.84.3.774. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Derynck R., Jarrett J. A., Chen E. Y., Goeddel D. V. The murine transforming growth factor-beta precursor. J Biol Chem. 1986 Apr 5;261(10):4377–4379. [PubMed] [Google Scholar]
  13. Dynan W. S., Tjian R. Control of eukaryotic messenger RNA synthesis by sequence-specific DNA-binding proteins. 1985 Aug 29-Sep 4Nature. 316(6031):774–778. doi: 10.1038/316774a0. [DOI] [PubMed] [Google Scholar]
  14. Eadie J. S., Conrad M., Toorchen D., Topal M. D. Mechanism of mutagenesis by O6-methylguanine. Nature. 1984 Mar 8;308(5955):201–203. doi: 10.1038/308201a0. [DOI] [PubMed] [Google Scholar]
  15. Eisenstadt E., Warren A. J., Porter J., Atkins D., Miller J. H. Carcinogenic epoxides of benzo[a]pyrene and cyclopenta[cd]pyrene induce base substitutions via specific transversions. Proc Natl Acad Sci U S A. 1982 Mar;79(6):1945–1949. doi: 10.1073/pnas.79.6.1945. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Fuchs R. P., Schwartz N., Daune M. P. Hot spots of frameshift mutations induced by the ultimate carcinogen N-acetoxy-N-2-acetylaminofluorene. Nature. 1981 Dec 17;294(5842):657–659. doi: 10.1038/294657a0. [DOI] [PubMed] [Google Scholar]
  17. Galiègue-Zouitina S., Bailleul B., Ginot Y. M., Perly B., Vigny P., Loucheux-Lefebvre M. H. N2-guanyl and N6-adenyl arylation of chicken erythrocyte DNA by the ultimate carcinogen of 4-nitroquinoline 1-oxide. Cancer Res. 1986 Apr;46(4 Pt 1):1858–1863. [PubMed] [Google Scholar]
  18. Guerrero I., Pellicer A. Mutational activation of oncogenes in animal model systems of carcinogenesis. Mutat Res. 1987 May;185(3):293–308. doi: 10.1016/0165-1110(87)90021-2. [DOI] [PubMed] [Google Scholar]
  19. Hennings H., Shores R., Wenk M. L., Spangler E. F., Tarone R., Yuspa S. H. Malignant conversion of mouse skin tumours is increased by tumour initiators and unaffected by tumour promoters. Nature. 1983 Jul 7;304(5921):67–69. doi: 10.1038/304067a0. [DOI] [PubMed] [Google Scholar]
  20. Ishii S., Merlino G. T., Pastan I. Promoter region of the human Harvey ras proto-oncogene: similarity to the EGF receptor proto-oncogene promoter. Science. 1985 Dec 20;230(4732):1378–1381. doi: 10.1126/science.2999983. [DOI] [PubMed] [Google Scholar]
  21. Jetten A. M., Shirley J. E., Stoner G. Regulation of proliferation and differentiation of respiratory tract epithelial cells by TGF beta. Exp Cell Res. 1986 Dec;167(2):539–549. doi: 10.1016/0014-4827(86)90193-x. [DOI] [PubMed] [Google Scholar]
  22. Klein G., Klein E. Oncogene activation and tumor progression. Carcinogenesis. 1984 Apr;5(4):429–435. doi: 10.1093/carcin/5.4.429. [DOI] [PubMed] [Google Scholar]
  23. Leon J., Guerrero I., Pellicer A. Differential expression of the ras gene family in mice. Mol Cell Biol. 1987 Apr;7(4):1535–1540. doi: 10.1128/mcb.7.4.1535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Masui T., Wakefield L. M., Lechner J. F., LaVeck M. A., Sporn M. B., Harris C. C. Type beta transforming growth factor is the primary differentiation-inducing serum factor for normal human bronchial epithelial cells. Proc Natl Acad Sci U S A. 1986 Apr;83(8):2438–2442. doi: 10.1073/pnas.83.8.2438. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Parkinson E. K. Defective responses of transformed keratinocytes to terminal differentiation stimuli. Their role in epidermal tumour promotion by phorbol esters and by deep skin wounding. Br J Cancer. 1985 Oct;52(4):479–493. doi: 10.1038/bjc.1985.219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Quintanilla M., Brown K., Ramsden M., Balmain A. Carcinogen-specific mutation and amplification of Ha-ras during mouse skin carcinogenesis. Nature. 1986 Jul 3;322(6074):78–80. doi: 10.1038/322078a0. [DOI] [PubMed] [Google Scholar]
  27. Rhim J. S., Fujita J., Arnstein P., Aaronson S. A. Neoplastic conversion of human keratinocytes by adenovirus 12-SV40 virus and chemical carcinogens. Science. 1986 Apr 18;232(4748):385–388. doi: 10.1126/science.2421406. [DOI] [PubMed] [Google Scholar]
  28. Scribner J. D., Scribner N. K., McKnight B., Mottet N. K. Evidence for a new model of tumor progression from carcinogenesis and tumor promotion studies with 7-bromomethylbenz[a]anthracene. Cancer Res. 1983 May;43(5):2034–2041. [PubMed] [Google Scholar]
  29. Sporn M. B., Roberts A. B., Wakefield L. M., Assoian R. K. Transforming growth factor-beta: biological function and chemical structure. Science. 1986 Aug 1;233(4763):532–534. doi: 10.1126/science.3487831. [DOI] [PubMed] [Google Scholar]
  30. Tanaka T., Slamon D. J., Battifora H., Cline M. J. Expression of p21 ras oncoproteins in human cancers. Cancer Res. 1986 Mar;46(3):1465–1470. [PubMed] [Google Scholar]
  31. Taparowsky E., Suard Y., Fasano O., Shimizu K., Goldfarb M., Wigler M. Activation of the T24 bladder carcinoma transforming gene is linked to a single amino acid change. Nature. 1982 Dec 23;300(5894):762–765. doi: 10.1038/300762a0. [DOI] [PubMed] [Google Scholar]
  32. Weinberg R. A. The action of oncogenes in the cytoplasm and nucleus. Science. 1985 Nov 15;230(4727):770–776. doi: 10.1126/science.2997917. [DOI] [PubMed] [Google Scholar]
  33. Yuspa S. H., Morgan D. L. Mouse skin cells resistant to terminal differentiation associated with initiation of carcinogenesis. Nature. 1981 Sep 3;293(5827):72–74. doi: 10.1038/293072a0. [DOI] [PubMed] [Google Scholar]
  34. Zarbl H., Sukumar S., Arthur A. V., Martin-Zanca D., Barbacid M. Direct mutagenesis of Ha-ras-1 oncogenes by N-nitroso-N-methylurea during initiation of mammary carcinogenesis in rats. 1985 May 30-Jun 5Nature. 315(6018):382–385. doi: 10.1038/315382a0. [DOI] [PubMed] [Google Scholar]

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