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Breast Cancer Research and Treatment

, Volume 50, Issue 1, pp 11–25 | Cite as

Genomic organization of the canine p53 gene and its mutational status in canine mammary neoplasia

  • Lee Lee Chu
  • Gerard R. Rutteman
  • Julius M.C. Kong
  • Majid Ghahremani
  • Martin Schmeing
  • Wim Misdorp
  • Evert van Garderen
  • Jerry Pelletier
Article

Abstract

To determine whether canine malignancies share common genetic lesions with their human counterparts, and are thus potentially interesting model systems in which to pose questions regarding tumor etiology and progression, we have elucidated the entire exon/intron structure of the canine p53 gene. A search for p53 gene abnormalities in mammary tumor tissue was undertaken utilizing single strand conformation polymorphism analysis. Mutations were detected in exons 4, 5, 6, and 7 of the p53 gene and consisted of nonsense, splicing, and frameshift mutations. None of 11 benign tumors and 6 of 40 primary carcinomas (15%) were found to harbor subtle p53 mutations. In 14 carcinomas examined the results in primary tumors and metastases were the same. These findings implicate involvement of this gene in the genesis of some malignant canine tumors, in a fashion similar to their human counterparts.

p53 breast cancer canine mutational analysis 

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References

  1. 1.
    Feuer E, Wun L, Boring C, Flanders W, Timmel M, Tong T: The lifetime risk of developing breast cancer. J Natl Cancer Inst 85: 892–897, 1993Google Scholar
  2. 2.
    Claus EB, Schildkraut JM, Thompson WD, Risch NJ: The genetic attributable risk of breast and ovarian cancer. Cancer 77: 2318–2324, 1997Google Scholar
  3. 3.
    Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA, Huey B, King M-C: Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250: 1684–1689, 1990Google Scholar
  4. 4.
    Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W, Bell R, Rosenthal J, Hussey C, Tran T, McClure M, Frye C, Hattier T, Phelps R, Haugen-Strano A, Katcher H, Yakumo K, Gholami Z, Shaffer D, Stone S, Bayer S, Wray C, Bogden R, Dayananth P, Ward J, Tonin P, Narod S, Bristow PK, Norris FH, Helvering L, Morrison P, Rosteck P, Lai M, Barrett C, Lewis C, Neuhausen S, Cannon-Albright L, Goldgar D, Wiseman R, Kamb A, Skolnick MH: A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266: 66–71, 1994Google Scholar
  5. 5.
    Wooster R, Neuhausen SL, Mangion J, Quirk Y, Ford D, Collins N, Nguyen K, Seal S, Tran T, Averill D, Fields P, Marshall G, Narod Sm Lenoir G, Lynch H, Feunteun J, Devilee P, Cornelisse CJ, Menko FH, Daly PA, Ormiston W, McManus R, Pye C, Lewis CM, Cannon-Albright LA, Peto J, Ponder BAJ, Skolnick MH, Easton DF, Goldgar DE, Stratton MR: Localization of a breast cancer susceptibility gene. BRCA2, to chromosome 13q12. Science 265: 2088–2090, 1994Google Scholar
  6. 6.
    Tavtigian SV, Simard J, Rommens J, Couch F, Shattuck-Eidens D, Neuhausen S, Merajver S, Thorlacius S, Offit K, Stoppa-Lyonnet D, Belanger C, Bell R, Berry S, Bogden R, Chen Q, Davis T, Dumont M, Frye C, Hattier T, Jammulapati S, Janecki T, Jiang P, Kehrer R, Leblanc J-F, Mitchell JT, McArthur-Morrison J, Nguyen K, Peng Y, Samson C, Schroeder M, Snyder SC, Steele L, Stringtellow M, Stroup C, Swedlund B, Swensen J, Teng D, Thomas A, Tran T, Tranchant M, Weaver-Feldhaus J, Wong AKC, Shizuya H, Eyfjord JE, Cannon-Albright L, Labrie F, Skolnick MH, Weber B, Kamb A, Goldgar DE: The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat Genet 12: 333–337, 1996Google Scholar
  7. 7.
    Malkin D, Li FP, Strong LC, Fraumeni JF, Nelsen CF, Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA, Friend SH: Germline p53 mutations in a familial syndrome of breast cancer, sarcomas and other neoplasms. Science 250: 1233–1238, 1990Google Scholar
  8. 8.
    Srivastava S, Zou ZQ, Pirollo K, Blattner W, Chang EH: Germline transmission of a mutated p53 gene in a cancerprone family with Li-Fraumeni syndrome. Nature 348: 747–749, 1990Google Scholar
  9. 9.
    Greenblatt MS, Bennett WP, Hollstein M, Harris CC: Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 54: 4855–4878, 1994Google Scholar
  10. 10.
    Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh W, Wigler MH, Parsons R. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275: 1943–1947, 1997Google Scholar
  11. 11.
    Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DHF, Tavtigian SV: Identification of a candidate tumor suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 15: 356–362, 1997Google Scholar
  12. 12.
    Cardiff RD, Muller WJ: Transgenic mouse models of mammary tumorigenesis. Cancer Surveys 16: 97–113, 1993Google Scholar
  13. 13.
    Chrisp CE, Spangler WL: The malignant canine mammary tumor as a model for the study of human breast cancer. In: Shifrine M, Wilson FD (eds) The Canine as a Biomedical Research Model: Immunological, Hematological, and Oncological Aspects. Technical Information Center/U.S. Department of Energy, 1980, pp 331–349Google Scholar
  14. 14.
    Brodey RS, Goldschmidt MH, Roszel JR: Canine mammary gland neoplasms. J Am Animal Hos Assn 19: 61–90, 1983Google Scholar
  15. 15.
    MacEwen EG: Spontaneous tumours in dogs and cats: Models for the study of cancer biology and treatment. Cancer Met Rev 9: 125–136, 1990Google Scholar
  16. 16.
    Dorn CR, Taylor DO, Schneider R, Hibbard HH, Klauber MR: Survey of animal neoplasms in Alameda and Contra Costa Counties, California II. Cancer morbidity in dogs and cats from Alameda County. J Natl Cancer Inst 40: 307–318, 1968Google Scholar
  17. 17.
    Priester WA, McKay FW: The occurrence of tumors in domestic animals. NCI Monograph 54, Bethesda, MD. National Cancer Institute. 1980, pp 152–184Google Scholar
  18. 18.
    Misdorp W: Histological classification and further characterization of tumors in domestic animals. Adv Vet Sci Comp Med 20: 191–221, 1976Google Scholar
  19. 19.
    Schneider R: Comparison of age, sex and incidence rates in human and canine breast cancer. Cancer 26: 419–425, 1970Google Scholar
  20. 20.
    Rutteman GR: Contraceptive steroids and the mammary gland: Is there a hazard? — Insights from animal studies. Breast Cancer Res Treat 23: 29–41, 1992Google Scholar
  21. 21.
    Rutteman GR, Misdorp W: Hormonal background of canine and feline mammary tumors. J Reprod Fertil Suppl 47: 483–487, 1993Google Scholar
  22. 22.
    Madewell BR, Theilen GH: Tumors of the mammary gland. In: Thielen G, Madewell BR (eds) Veterinary Cancer Medicine. Lea & Febiger, Philadelphia, 1987, pp 327–344Google Scholar
  23. 23.
    MacEwen EG, Withrow SJ: Tumors of the mammary gland. In: Withrow SJ, MacEwen EG (eds) Small Animal Clinical Oncology. WB Saunders, Philadelphia, 1996, pp 356–372Google Scholar
  24. 24.
    Hellmén F., Lindgren A, Linell F, Matsson P, Nilsson A: Comparison of histology and clinical variables to DNA ploidy in canine mammary tumors. Vet Pathol 25: 219–226, 1988Google Scholar
  25. 25.
    Rutteman GR, Cornelisse CJ, Dijkshoorn NJ, Poortman J, Misdorp W: Flow cytometric analysis of DNA ploidy in canine mammary tumors. Cancer Res 48: 3411–3417, 1988Google Scholar
  26. 26.
    Pérez-Alenza MD, Rutteman GR, Kuipers-Dijkshoorn NJ, Pena L, Montoya A, Misdorp W, Cornelisse CJ: DNA flow cytometry of canine mammary tumours: the relationship of DNA ploidy and S-phase fraction to clinical and histological features. Res Vet Sci 58: 238–243, 1995Google Scholar
  27. 27.
    MacEwen EG, Panko WB, Patnaik AK, Harvey HJ: Estrogen receptor in canine mammary tumors. Cancer Res 42: 2255–2259, 1982Google Scholar
  28. 28.
    Caron de Fromental C, Soussi T: TP53 tumor suppressor gene: A model for investigating human mutagenesis. Genes Chrom Cancer 4: 1–15, 1992Google Scholar
  29. 29.
    Hollstein M, Sidransky D, Vogelstein B, Harris CC: p53 mutations in human cancers. Science 253: 49–53, 1991Google Scholar
  30. 30.
    Van Leeuwen IS, Hellmen E, Cornelisse CJ, Van den Burgh B, Rutteman G: P53 mutations in mammary tumor cell lines and corresponding tumor tissues in the dog. Anticancer Res 16: 3737–3744, 1996Google Scholar
  31. 31.
    Hampe JJ, Misdorp W: Tumors and dysplasias of the mammary gland. Bull WHO 50: 111–133, 1974Google Scholar
  32. 32.
    Sambrook J, Fritsch EF, Maniatis T: Molecular Cloning. A Laboratory Manual. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 1989Google Scholar
  33. 33.
    Sanger AF, Nicklen S, Coulson AR: DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA 74: 5463–5467, 1997Google Scholar
  34. 34.
    Orita M, Suzuki Y, Sekiya T, Hayashi K: Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Genomics 5: 874–879, 1989Google Scholar
  35. 35.
    Liu Q, Sommer SS: Parameters affecting the sensitivities of dideoxy fingerprinting and SSCP. PCR Methods Appl 4: 97–108, 1994Google Scholar
  36. 36.
    Kraegel SA, Pazzi KA, Madewell BR: Sequence analysis of canine p53 in the regions of exons 3–8. Cancer Lett 92: 181–186, 1995Google Scholar
  37. 37.
    Shaulsky G, Goldfinger N, Ben Ze'ev A, Rotter V: Nuclear accumulation of p53 protein is mediated by several nuclear localization signals and plays a role in tumorigenesis. Mol Cell Biol 10: 6565–6577, 1990Google Scholar
  38. 38.
    Milner J, Medcalf EA: Cotranslation of activated mutant p53 with wild-type drives the wild-type p53 protein into the mutant conformation. Cell 65: 765–774, 1991Google Scholar
  39. 39.
    Mayr B, Schellander K, Schleger W, Reifinger M: Sequence of an exon of the canine p53 gene — mutation in a papilloma. Br Vet J 150: 81–84, 1994Google Scholar
  40. 40.
    Devilee P, Van Leeuwen IS, Voesten A, Rutteman GR, Vos JH, Cornelisse CJ: The canine p53 gene is subject to somatic mutations in thyroid carcinoma. Anticancer Res 14: 2039–2046, 1994Google Scholar
  41. 41.
    Van Leeuwen IS, Cornelisse CJ, Misdorp W, Goedegebuure SA, Kirpensteijn J, Rutteman GR: P53 gene mutations in osteosarcomas in the dog. Cancer Lett 111: 173–178, 1997Google Scholar
  42. 42.
    Veldhoen N, Stewart J, Brown R, Milner J: Mutations of the p53 gene in canine lymphoma and evidence for germline p53 mutations in the dog. Oncogene 16: 249–255, 1997Google Scholar
  43. 43.
    Greenblatt MS, Bennett WP, Hollstein M, Harris CC: Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 54: 4855–4878, 1994Google Scholar
  44. 44.
    Casey G, Lopez ME, Ramos JC, Plummer SJ, Arboleda MJ, Shaughnessy M, Karlan B, Slamon DJ: DNA sequence analysis of exons 2 through 11 and immunohistochemical staining are required to detect all known p53 alterations in human malignancies. Oncogene 13: 1971–1981, 1996Google Scholar
  45. 45.
    Tsuda H, Iwaya K, Fukutomi T, Hirohashi S: p53 mutations and c-erb-B-2 amplification in intraductal and invasive breast carcinomas of high histologic grade. Jpn J Cancer 84: 394–401Google Scholar
  46. 46.
    Gamblin RM, Sagartz JE, Couto CG: Over-expression of p53 tumor suppressor protein in spontaneously arising neoplasms of dogs. Am J Vet Res 58: 857–863, 1997Google Scholar
  47. 47.
    Veldhoen N, Milner J: Isolation of canine p53 cDNA and detailed characterization of the full length canine p53 protein. Oncogene 16: 1077–1084, 1998Google Scholar
  48. 48.
    Okuda M, Umeda A, Sakai T, Ohashi T, Momoi Y, Youn HY, Watari T, Goitsuka R, Tsujimoto H, Hasegawa A: Cloning of feline p53 tumor-suppressor gene and its aberration in hematopoietic tumors. Int J Cancer 58: 602–607, 1994Google Scholar
  49. 49.
    Bronson RT: Variation in age at death of dogs of different sexes and breeds. Am J Vet Res 43: 2057–2059, 1982Google Scholar
  50. 50.
    Harlow E, Williamson NM, Ralston R, Helfman DM, Adams TE: Molecular cloning and in vitro expression of a cDNA clone for human cellular tumor antigen p53. Mol Cell Biol 5: 1601–1610, 1985Google Scholar
  51. 51.
    Arai N, Nomura D, Yokota K, Wolf D, Brill E, Shohat O, Rotter V: Immunologically distinct p53 molecules generated by alternative splicing. Mol Cell Biol 6: 3232–3239, 1986Google Scholar
  52. 52.
    Auffray C, Rougeon F: Purification of mouse immunoglobulin heavy-chain messenger RNAs from total myeloma tumor RNA. Eur J Biochem 107: 303–314, 1980Google Scholar

Copyright information

© Kluwer Academic Publishers 1998

Authors and Affiliations

  • Lee Lee Chu
    • 1
  • Gerard R. Rutteman
    • 2
  • Julius M.C. Kong
    • 1
  • Majid Ghahremani
    • 1
  • Martin Schmeing
    • 1
  • Wim Misdorp
    • 2
    • 3
  • Evert van Garderen
    • 4
  • Jerry Pelletier
    • 1
    • 5
  1. 1.Department of BiochemistryCanada
  2. 2.Department of Clinical Sciences of Companion AnimalsNetherlands
  3. 3.Department of Pathology, Faculty of Veterinary MedicineUniversity of UtrechtNetherlands
  4. 4.Department of Pathology, Faculty of Veterinary MedicineUniversity of UtrechtNetherlands
  5. 5.Department of OncologyMcGill UniversityMontréalCanada

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