Transgenic Research

, Volume 7, Issue 4, pp 253–263

Lactation-induced WAP-SV40 Tag Transgene Expression in C57BL/6J Mice Leads to Mammary Carcinoma

  • Margaret R. Hüsler
  • Kristin A. Kotopoulis
  • John P. Sundberg
  • Barabara J. Tennent
  • Sabine V. Kunig
  • Barabara B. Knowles


Two transgenic lineages were generated by directing the expression of SV40 T antigen to the mammary gland of inbred C57BL/6J mice using the whey acidic protein (WAP) promoter. In one lineage, WAPTag 1, multiparous female mice developed mammary adenocarcinoma with an average latency period of 13 months. The histopathological phenotype was heterogeneous, tumours occurred in a stochastic fashion, normal tissue was located next to neoplastic tissue, the mammary tumours usually developed and were remarkably similar to that observed in human cases. In addition, male and virgin females developed a poorly differentiated SV40 T antigen-positive soft tissue sarcoma, also at 13 months of age. In the other lineage, WAPTag 3, some parous females developed mammary tumours, but most mice succumbed to osteosarcomas arising from the os petrosum at 5.5 to 6 months of age and on necropsy, renal adenocarcinomas were also found. Appearance of these unexpected tumour types demonstrates the non-specific e...

mammary carcinoma sarcoma transgenic mouse simian virus 40 T-antigen whey acidic protein C57BL/6J 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adams, J.M. and Cory S. (1991) Transgenic models of tumor development. Science 254, 1161–6.Google Scholar
  2. Andres, A.C., Schönenberger, C.A., Gronor, B., Hennighausen, L., LeMeur, M. and Gerlinger, P. (1987) Ha-ras oncogene expression directed by a milk protein gene promoter: tissue specificity, hormonal regulation and tumor induction in transgenic mice. Proc. Natl Acad. Sci. USA 84, 1299–303.Google Scholar
  3. Behringer, R.R., Peschon, J.J., Messing, A., Gartside, C.L., Hauschka, S.D., Palmiter, R.D. and Brinster R.L. (1988) Heart and bone tumors in transgenic mice. Proc. Natl Acad. Sci. USA 85, 2648–52.Google Scholar
  4. Birch, J.M. (1994) Li-Fraumeni syndrome. European J. Cancer 30A, 1935–41.Google Scholar
  5. Bièche, I. and Lidereau, R. (1995) Genetic alterations in breast cancer. Genes Chromosomes Cancer 14, 227–51.Google Scholar
  6. Brandazza, A., Lee, E., Ferrara, M., Tillman, U., Sarmientos, P. and Westphal, H. (1991) Use of the urokinase-type plasminogen activator gene as a general tool to monitor expresion in transgenic animals: study of the tissue-specificity of the murine whey acidic protein (WAP) expression signals. J. Biotechnology 20, 201–12.Google Scholar
  7. Brinster, R.L., Chen, H.Y., Messing, A., van Dyke, T., Levine, A.J. and Palmiter, R.D. (1984) Transgenic mice harboring SV40 T-antigen genes develop characteristic brain tumors. Cell 37, 367–79.Google Scholar
  8. Cardiff, R.D. and Muller, W.J. (1993) Transgenic mouse models of mammary tumorigenesis. Cancer Surveys 16, 97–113.Google Scholar
  9. Cardiff, R.D. and Munn, R.J. (1995) Comparative pathology of tumorigenesis in transgenic mice. Cancer Lett. 90, 13–9.Google Scholar
  10. Chan, T., Lin, A., McNally, J., Peleg, D., Meyuhas, O. and Wool, I.G. (1987) The primary structure of rat ribosomal protein L19. J. Bio. Chem. 262, 1111–5.Google Scholar
  11. Chomczynski, P. and Sacchi, N. (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162, 156–9.Google Scholar
  12. Conzen, S.D. and Cole, C.N. (1995) The three transforming regions of SV40 T antigen are required for immortalization of primary mouse embryo fibroblasts. Oncogene 11, 2295–302.Google Scholar
  13. Dankort, D.L. and Muller, W.J. (1996) Transgenic models of breast cancer metastasis. Cancer Treat. Res. 83, 71–88.Google Scholar
  14. DeCaprio, J.A., Ludlow, J.W., Figge, J., Shew, J.Y., Huang, C.M., Lee, W.H., Marsilio, E., Paucha, E. and Livingston, D.M. (1988) SV40 large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene. Cell 54, 275–83.Google Scholar
  15. Draper, G.J., Sanders, B.M. and Kingston, J.E. (1986) Second primary neoplasm in patients with retinoblastoma. Br. J. Cancer 53, 661–71.Google Scholar
  16. Ewald, D., Li, M., Efrat, S., Auer, G., Wall, R.J., Furth, P.A. and Hennighausen, L. (1996) Time-sensitive reversal of hyperplasia in transgenic mice expressing SV40 T antigen. Science 273, 1384–6.Google Scholar
  17. Faas, S.J., Pan, S., Pinkert, C.A., Brinster, R.L. and Knowles, B.B. (1987) Simian virus 40 (SV40)-transgenic mice that develop tumours are specifically tolerant to SV40 T antigen. J. Exp. Med. 165, 417–27.Google Scholar
  18. Fanning, E. and Knippers, R. (1992) Structure and function of simian virus 40 large tumor antigen. Annu. Rev. Biochem. 61, 55–85.Google Scholar
  19. Graessmann, M., Guhl, E., Bumke-Vogt, C. and Graessmann, A. (1984) The second large simian virus 40 T-antigen exon contains the information for maximal cell transformaion. J. Mol. Biol. 180, 111–29.Google Scholar
  20. Greenberg, N.M., DeMayo, F., Finegold, J.J., Medina, D., Tilley, W.D., Aspinall, J.O., Cunha, G.R., Donjacour, A.A., Matusik R.J. and Rosen, J.M. (1995) Prostate cancer in a transgenic mouse. Proc. Natl Acad. Sci. USA 92, 3439–43.Google Scholar
  21. Günzburg, W.H., Salmons, B., Zimmermann, B., Müller, M., Erfle, V. and Brem, G. (1991) A mammary-specific promoter directs expression of growth hormone not only to the mammary gland but also to Bergman glia cells in transgenic mice. Mol. Endocrinol. 55, 123–32.Google Scholar
  22. Hanahan, D. (1985) Heritable formation of beta-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature 315, 115–22.Google Scholar
  23. Hennighausen, L.G. and Sippel, A.E. (1982) Mouse whey acidic protein is a novel member of the family of four-disulfide core proteins. Nucl. Acids Res. 10, 2677–88.Google Scholar
  24. Hobbs, A.A., Richards, D.A., Kessler, D.J. and Rosen, J.M. (1982) Complex hormonal regulation of rat casein gene expression. J. Biol. Chem. 257, 3598–605.Google Scholar
  25. Jacks, T. (1996) Lessons from the p53 mutant mouse. J. Cancer Res. Clin. Oncol. 122, 319–27.Google Scholar
  26. Knowles, B.B., Koncar, M., Pfizenmaier, K., Solter, D., Aden, D.P. and Trinchieri, G. (1979) Genetic control of the cytotoxic T cell response to SV40 tumor-associated specific antigen. J. Immunol. 122, 1798–806.Google Scholar
  27. Knowles, B.B., McCarrick, J., Fox, N., Solter, D. and Damjanov, I. (1990) Osteosarcomas in transgenic mice expressing and α-amylase-SV40 T-antigen hybrid gene. Am. J. Pathol. 137, 258–62.Google Scholar
  28. LaFond, R.E., Giammalvo, J.T. and Norkin, L.C. (1995) Relationship between expression of epidermal growth factor and simian virus 40 T antigen in a line of transgenic mice, Transgenic Res. 4, 306–14.Google Scholar
  29. Li, S. and Rosen, J.M. (1994) Distal regulatory elements are required for rat whey acidic protein gene expression in transgenic mice. J. Biol. Chem. 269, 14235–43.Google Scholar
  30. Liu, P.K., Kraus, E., Wu, T.A., Strong, L.C. and Tainsky, M. (1996) Analysis of genomic instability in Li-Fraumeni fibroblasts with germline p53 mutations. Oncogene 12, 2267–78.Google Scholar
  31. Mahon, K.A., Chepelinsky, A.B., Khillan, J.S., Overbeek, P.A., Piatigorsky, J. and Westphal, H. (1987) Oncogenesis of the lens in transgenic mice. Science 235, 1622–8.Google Scholar
  32. Maroulakou, I.G., Anver, M., Garrett, L. and Green, G.E. (1994) Prostate and mammary adenocarcinoma in transgenic mice carrying a rat C3(1) simian virus 40 large tumor antigen fusion gene. Proc. Natl Acad. Sci. USA 91, 11236–40.Google Scholar
  33. Messing, A., Chen, H.Y., Palmiter, R.D. and Brinster, R.L. (1985) Peripheral neuropathies, hepatocellular carcinoma and islet cell adenomas in transgenic mice. Nature 316, 461–3.Google Scholar
  34. Miller, C.W., Aslo, A., Won, A., Tan, M., Lampkin, B. and Koeffler, H.P. (1996) Alterations of the p53, Rb and MDM2 genes in osteosarcoma. J. Cancer Res. Clin. Oncol. 122, 559–65.Google Scholar
  35. Oliner, J.D., Kinzler, K.W., Meltzer, P.S., George, D.L. and Vogelstein, B. (1992) Amplification of a gene encoding a p53–associated protein in human sarcomas Nature 358, 80–3.Google Scholar
  36. Ornitz, D.M., Hammer, R.E., Messing, A., Palmiter, R.D. and Brinster, R.L. (1987) Pancreatic neoplasia induced by SV40 T antigen expression in acinar cells of transgenic mice. Science 238, 188–93.Google Scholar
  37. Page, D.L. and Dupont, W.D. (1993) Anatomic indicators (histological and cytologic) of increased breast cancer risk. Breast Cancer Res. Treat. 28, 157–66.Google Scholar
  38. Pittius, C.W., Sankaran, L., Topper, Y.J. and Henninghausen, L. (1988) Comparison of the regulation of the whey acidic protein gene with that of a hybrid gene containing the whey acidic protein promoter in transgenic mice. Mol. Endocrinol. 2, 1027–32.Google Scholar
  39. Reynolds, R.K., Hoekzema, G.S., Vogel, J., Hinrichs, S. and Jay, G. (1988) Multiple endocrine neoplasia induced by the promiscuous expression of a viral oncogene. Proc. Natl Acad. Sci. USA 85, 3135–9.Google Scholar
  40. Robinson, G.W., McKnight, R.A., Smith G.H. and Hennighausen, L. (1995) Mammary epithelial cells undergo secretory differentiation in cycling virgins but require pregnancy for the establishment of terminal differentiation. Develop. 121, 2079–90.Google Scholar
  41. Sandgren, E.P., Quaife, C.J., Pinkert, C.A., Palmiter, R.D. and Brinster, R.L. (1989) Oncogene-induced liver neoplasia in transgenic mice. Oncogene 4, 715–24.Google Scholar
  42. Santarelli, R., Tzeng, Y.J., Zimmermann, C., Guhl, E. and Graessmann, A. (1996) SV40 T-antigen induces breast cancer formation with a high efficiency in lactating and virgin WAPSV-T transgenic animals but with a low efficiency in ovariectomized animals. Oncogene 12, 495–505.Google Scholar
  43. Skalnick, D.G., Dorfman, D.M., Williams, D.A. and Orkin, S.H. (1991) Restriction of neuroblastoma to the prostate gland in transgenic mice. Mol. Cell Biol. 11, 4518–27.Google Scholar
  44. Squartini, F. (1979) Tumors of the mammary gland. In Tutusov, V.S. ed., Pathobiology of Tumors in Laboratory Animals, Vol. 2, Lyon, France: International Agency of Research on Cancer, pp. 43–90.Google Scholar
  45. Steeg, P.S., Clare, S.E., Lawrence, J.A. and Zhou W. (1996) Molecular analysis of premalignant and carcinoma in situ lesions of the human breast. Am. J. Pathol. 149, 733–8.Google Scholar
  46. Sundberg, J.P., Hanson, C.A., Roop, D.R., Brown, K.S. and Bedigian, H.G. (1991) Myoepitheliomas in inbred laboratory mice. Bet. Pathol. 28, 313–23.Google Scholar
  47. Sundberg, J.P., Erickson, A.A., Roop, D.R. and Binder, R.L. (1994) Ornithine decarboxylase expression in cutaneous papillomas in SENCAR mice is associated with altered expression of keratins K1 and K10. Cancer Res. 54, 1344–51.Google Scholar
  48. T'ang, A., Varley, J.M., Chakraborty, S., Murphree, A.L. and Fung, Y-K.T. (1988) Structural rearrangement of the retinoblastoma gene in human breast carcinoma. Science 242, 263–6.Google Scholar
  49. Teixeira, M.R., Pandis, N., Bardi, G., Andersen, J.A., Mitelman, F. and Heim, S. (1995) Clonal heterogeneity in breast cancer: karyotypic comparison of multiple intra-and extra-tumorous samples from 3 patients. Int. J. Cancer 63, 63–8.Google Scholar
  50. Tzeng, Y.J., Guhl, E., Graessmann, M. and Graessmann, A. (1993) Breast cancer formation in transgenic animals induced by the whey acidic protein SV40 T antigen (WAP-SV-T) hybrid gene. Oncogene 8, 1965–71.Google Scholar
  51. Varley, J.M., Armour, J., Swallow, J.E., Jefreys, A.J., Ponder, B.A.J., T'ang, A., Fung, Y-K.T., Brammar, W.J. and Walker, R.A. (1989) The retinoblastoma gene is frequently latered leading to loss of expression in primary breast cancer. Oncogene 4, 725–9.Google Scholar
  52. Vonderhaar, B.K. and Ziska, S.E. (1989) Hormonal regulation of milk protein gene expression. Annu. Rev. Physiol. 51, 641–52.Google Scholar
  53. Wen, J., Kawamata, Y., Tojo, H., Tanaka, S. and Tachi, C. (1995) Expression of whey acidic protein (WAP) genes in tissues other than the mammary gland in normal and transgenic mice expressing mWAP/hGH fusion gene. Mol. Reprod. Dev. 41, 399–406.Google Scholar
  54. Wilkie, T.M., Schmidt, R.A., Baetscher, M. and Messing, A. (1994) Smooth muscle and bone neoplasms in trangenic mice expressing SV40 T antigen. Oncogene 9, 2889–95.Google Scholar
  55. Ye, X., McCarrick, J., Jewett, L. and Knowles, B.B. (1994) Timely immunization subverts the development of peripheral non-responsiveness and suppresses tumor development in simian virus 40 tumor antigen-transgenic mice. Proc. Natl Acad. Sci. USA 91, 3916–20.Google Scholar
  56. Ye, X., Kralli, A., Ge, R., Ricciardi, R.P. and Knowles, B.B. (1994) Down-regulation of MHC class I antigen in insulinoma cells controlled by the R1 element of the H-2 enhancer. Oncogene 9, 1195–204.Google Scholar

Copyright information

© Kluwer Academic Publishers 1998

Authors and Affiliations

  • Margaret R. Hüsler
  • Kristin A. Kotopoulis
  • John P. Sundberg
  • Barabara J. Tennent
  • Sabine V. Kunig
  • Barabara B. Knowles

There are no affiliations available

Personalised recommendations