Skip to main content
Log in

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

  • Published:
Transgenic Research Aims and scope Submit manuscript

Abstract

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...

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Adams, J.M. and Cory S. (1991) Transgenic models of tumor development. Science 254, 1161–6.

    Google Scholar 

  • 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 

  • 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 

  • Birch, J.M. (1994) Li-Fraumeni syndrome. European J. Cancer 30A, 1935–41.

    Google Scholar 

  • Bièche, I. and Lidereau, R. (1995) Genetic alterations in breast cancer. Genes Chromosomes Cancer 14, 227–51.

    Google Scholar 

  • 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 

  • 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 

  • Cardiff, R.D. and Muller, W.J. (1993) Transgenic mouse models of mammary tumorigenesis. Cancer Surveys 16, 97–113.

    Google Scholar 

  • Cardiff, R.D. and Munn, R.J. (1995) Comparative pathology of tumorigenesis in transgenic mice. Cancer Lett. 90, 13–9.

    Google Scholar 

  • 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 

  • 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 

  • 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 

  • Dankort, D.L. and Muller, W.J. (1996) Transgenic models of breast cancer metastasis. Cancer Treat. Res. 83, 71–88.

    Google Scholar 

  • 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 

  • 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 

  • 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 

  • 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 

  • Fanning, E. and Knippers, R. (1992) Structure and function of simian virus 40 large tumor antigen. Annu. Rev. Biochem. 61, 55–85.

    Google Scholar 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • Jacks, T. (1996) Lessons from the p53 mutant mouse. J. Cancer Res. Clin. Oncol. 122, 319–27.

    Google Scholar 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • Vonderhaar, B.K. and Ziska, S.E. (1989) Hormonal regulation of milk protein gene expression. Annu. Rev. Physiol. 51, 641–52.

    Google Scholar 

  • 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 

  • 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 

  • 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 

  • 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 

Download references

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hüsler, M.R., Kotopoulis, K.A., Sundberg, J.P. et al. Lactation-induced WAP-SV40 Tag Transgene Expression in C57BL/6J Mice Leads to Mammary Carcinoma. Transgenic Res 7, 253–263 (1998). https://doi.org/10.1023/A:1008865911660

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1008865911660

Navigation