ras Oncogenes pp 199-210 | Cite as

Tumorigenic Conversion of in vivo Differentiation Competent Mammary Cells by Introduction and Expression of ras or mil(raf) but not myc

  • Walter H. Günzburg
  • Brian Salmons
  • Robert Ullrich


Mammary cancer affects around 9% of women and is the most frequent cause of death in women aged between 40 to 54 years old (Miller and Bulbrook, 1986). Whilst the mechanisms involved in mammary tumorigene fs are not understood, there is evidence for the existence of a human mammary tumour virus that is related to the Mouse Mammary Tumour Virus (MMTV) (Schlom et al., 1971; Crepin et al., 1984; Keydar et al., 1984; Ono et al., 1986; Ono et al., 1987; Franklin et al., 1988). Additionally, a number of oncogenes have been implicated in the tumorigenic process. Elevated expression and/or amplification of the oncogenes ras, myc and neu have been correlated with human mammary tumorigenesis (Horan-Hand et al., 1984; DeBortoli et al., 1985; Ohuchi et al., 1986; Kraus et al., 1984; King et al., 1985; Slamon et al., 1987; Kozbor and Croces, 1984; Escot et al., 1986; Varley et al., 1987).


Mammary Gland Mammary Epithelial Cell Mammary Cancer Mouse Mammary Tumour Virus Mammary Tumorigenesis 
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  1. Ali, I.U., Campbell, G., Lidereau, R. and Callahan, R., 1988, Amplification of c-erbB-2 and aggressive human breast tumors? Science 240, 1795–1796.CrossRefGoogle Scholar
  2. Andres, A.C., Schoenenberger, C.A., Groner, B., Henninghausen, 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.PubMedCrossRefGoogle Scholar
  3. Asch, H.L. and Asch, B.B., 1985, Heterogeneity of keratin expression in mouse mammary hyperplastic alveolar nodules and adenocarcinomas. Cancer Res. 45, 2760–2768.PubMedGoogle Scholar
  4. Brown, A.M.C., Wildin, R. S., Prendergast, T.J. and Varmus, H.E., 1986, A retrovirus vector expressing the putative mammary oncogene int-1 causes partial transformation of a mammary epithelial cell line. Cell 46, 1001–1009.PubMedCrossRefGoogle Scholar
  5. Cepko, C.L., Roberts, B.E. and Mulligan, R.C., 1984, Construction and applications of a highly transmissible murine retrovirus shuttle vector. Cell 37, 1053–1062.PubMedCrossRefGoogle Scholar
  6. Crepin, M., Lidereau, R., Chermann, J. C., Pouillart, P., Magdamenat, H. and Montagnier, L., 1984, Sequences related to mouse mammary tumor virus genome in tumor cells and lymphocytes from patients with breast cancer. Biochem. Biophys. Res. Commun. 118, 324–331.PubMedCrossRefGoogle Scholar
  7. DeBortoli, M. E., Abou-Issa, H., Haley, B.E. and Cho-Chung, Y. S., 1985, Amplified expression of p21 ras protein in hormone-dependent mammary carcinomas of humans and rodents. Biochem. Biophys. Res. Commun. 127, 699–706.PubMedCrossRefGoogle Scholar
  8. Edwards, P.A.W., Ward, J.L. and Bradbury, J.M., 1988, Alteration of morph-ogenesis by the v-myc oncogene in transplants of mammary gland. Onco-gene 2, 407–412.Google Scholar
  9. Escot, C., Theillet, C., Lidereau, R., Spyratos, F., Champeme, M.H., Gest, J. and Callahan, R., 1986, Genetic alteration of the c-myc proto-oncogene (MYC) in human primary breast carcinomas. Proc. Natl. Acad. Sci. USA 83, 4834–4838.PubMedCrossRefGoogle Scholar
  10. Falcone, G., Summerhayes, I.C., Paterson, H., Marshall, C.J. and Hall, A., 1987, Partial transformation of mouse fibroblastic and epithelial cell lines with the v-myc oncogene. Exp. Cell Res. 168, 273–284.PubMedCrossRefGoogle Scholar
  11. Franklin, G.C., Chreitien, S., Hanson, I. M., Rochefort, H., May, F.E.B. and Westley, B., 1988, Expression of human sequences related to those of mouse mammary tumor virus. J. Virol. 62, 1203–1210.PubMedGoogle Scholar
  12. Gallahan, D. and Callahan, R., 1987, Mammary tumorigenesis in feral mice: Identification of a new int locus in mouse mammary tumor virus (Czech II) -induced mammary tumors. J. Virol. 61, 66–74.PubMedGoogle Scholar
  13. Gray, D.A., McGrath, C. M., Jones, R.F. and Morris, V. L., 1986, A common mouse mammary tumor virus integration site in chemically induced pre-cancerous mammary hyperplasias. Virology 148, 360–368.PubMedCrossRefGoogle Scholar
  14. Günzburg, W.H. and Salmons, B., 1986, Mouse mammary tumour virus mediated transfer and expression of neomycin resistance to infected cultured cells. Virology 155, 236–248.PubMedCrossRefGoogle Scholar
  15. Günzburg, W.H., Salmons, B., Sclaeffli, A., Moritz-Legrand, S., Jones, W., Sarkar, N.H. and Ullrich, R., 1988, Expression of the oncogenes mil and ras abolishes abolishes the in vivo differentiation of mammary epithe-lial cells. Carcinogenesis 9, 1849–1856.PubMedCrossRefGoogle Scholar
  16. Horan-Hand, P., Thor, A., Wunderlich, D., Muraro, R., Caruso, A. and Schlom, J., 1984, Monoclonal antibodies of predefined specificity detect activated ras gene expression in human mammary and colon car-cinomas. Proc. Natl. Acad. Sci. USA. 81, 5227–5231.CrossRefGoogle Scholar
  17. Hsiao, W-L.W., Lopez, C.A., Wu, T. and Weinstein, I.B., 1987, A factor present in fetal calf serum enhances oncogene-induced transformation of rodent fibroblasts. Mol. Cell. Biol. 7, 3380–3385.PubMedGoogle Scholar
  18. Ishikawa, F., Takaku, F., Ochiai, M., Hayashi, K., Hirohashi, S., Terada, M., Takayama, S., Nagao, M. and Sugimura, T., 1985, Activated c-raf gene in a rat hepatocellular carcinoma induced by 2-amino-3-methylimidazo[4,5-f]quinoline. Biochem. Biophys. Res. Commun. 132,186–192.PubMedCrossRefGoogle Scholar
  19. Keski-Oja, J., Rapp, U.R. and Vaheri, A., 1982, Transformation of mouse epithelial cells by acute murine leukaemia virus 3611: inhibition of collagen synthesis and induction of novel polypeptides. J. Cell. Biochem. 20, 139–148.PubMedCrossRefGoogle Scholar
  20. Keydar, I., Ohno, T., Nayak, R., Sweet, R., Simoni, F., Weiss, F., Karby, S., Mesa-Tejada, R. and Spiegelman, S., 1984, Properties of retrovirus-like particles produced by a human breast carcinoma cell line: immunological relationship with mouse mammary tumor virus proteins. Proc. Natl. Acad. Sci. USA. 81, 4188–4192.PubMedCrossRefGoogle Scholar
  21. King, C.R., Kraus, M.H. and Aaronson, S.A., 1985, Amplification of a novel v-erbB-related gene in a human mammary carcinoma. Science 229, 974–976.PubMedCrossRefGoogle Scholar
  22. Kozbor, D. and Croces, C.M., 1984, Amplification of the c-myc oncogene in one of five human breast carcinoma cell lines. Cancer Res. 44, 438–441.PubMedGoogle Scholar
  23. Kraus, M.H., Yuasa, Y. and Aaronson, S.A., 1984, A position 12-activated H-ras oncogene in all HS578T mammary carcinosarcoma cells but not normal mammary cells of the same patient. Proc. Natl. Acad. Sci. USA 81, 5384–5388.PubMedCrossRefGoogle Scholar
  24. Medina, D., 1988, The preneoplastic state in mouse mammary tumorigenesis. Carcinogenesis 9, 1113–1119.PubMedCrossRefGoogle Scholar
  25. Miller, A.B. and Bulbrook, R.D., 1986, UICC multidisciplinary project on breast cancer: the epidemiology, aetiology and prevention of breast cancer. Int. J. Cancer 37, 173–177.PubMedCrossRefGoogle Scholar
  26. Muller, W. J., Sinn, E., Pattengale, P. K., Wallace, R. and Leder, P., 1988, Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. Cell 54, 105–115.PubMedCrossRefGoogle Scholar
  27. Nusse, R. and Varmus, H.E., 1982, Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 31, 99–109.PubMedCrossRefGoogle Scholar
  28. Ohuchi, N., Thor, A., Page, D. L., Horan-Hand, P., Halter, S.A. and Schlom, J., 1986, Expression of the 21, 000 molecular weight ras protein in a spectrum of benign and malignant human mammary tissues. Cancer Res. 46, 2511–2519.PubMedGoogle Scholar
  29. Ono, M., Yasunaga, T., Miyata, T. and Ushikubo, H., 1986, Nucleotide sequence of human endogenous retrovirus genome related to the mouse mammary tumor virus genome. J. Virol. 60, 589–598.PubMedGoogle Scholar
  30. Ono, M., Kawakami, M. and Ushikubo, H., 1987, Stimulation of expression of the human endogenous retrovirus genome by female steroid hormones in human breast cancer cell line T47D. J.Virol. 61,2059–2062.PubMedGoogle Scholar
  31. Palmieri, S., Kahn, P. and Graf, T., 1983, Quail embryo fibroblasts transformed by four v-myc-containing virus isolates show enhanced proliferation but are non tumorigenic. The EMBO J. 2, 2385–2389.Google Scholar
  32. Peters, G., Brookes, S., Smith, R. and Dickson, C., 1983, Tumorigenesis by mouse mammary tumor virus: evidence for a common region for provirus integration in mammary tumors. Cell 33, 369–377.PubMedCrossRefGoogle Scholar
  33. Rudland, P.S., Bennett, D.C. and Warburton, M.J., 1987, Hormonal control of growth and differentiation of cultured rat mammary gland epithelial cells. Cold Spring Harbor Conf. on Cell Proliferation 6, 677–699.Google Scholar
  34. Salmons, B. and Günzburg, W.H., 1987, Current perspectives in the biology of mouse mammary tumour virus. Virus Research 8, 81–102.PubMedCrossRefGoogle Scholar
  35. Salomon, D. S., Perroteau, I., Kidwell, W.R., Tam, J. and Derynck, R., 1987, Loss of growth responsiveness to epidermal growth factor and enhanced production of alpha-transforming growth factors in ras-transformed mouse mammary epithelial cells. J. Cell. Physiol. 130, 397–409.PubMedCrossRefGoogle Scholar
  36. Schlom, J., Spiegelman, S. and Moore, D., 1971, RNA-dependent DNA polymerase activity in virus-like particles isolated from human milk. Nature 14, 231–298.Google Scholar
  37. Schoenenberger, C-A., Andres, A-C., Groner, B., van der Valk, M., LeMeur, M. and Gerlinger, P., 1988, Targeted c-myc gene expression in mammary glands of transgenic mice induces mammary tumours with constitutive milk protein gene transcription. The EMBO J. 7, 169–175.Google Scholar
  38. Shih, C. and Weinberg, R.A., 1982, Isolation of a transforming sequence from a human bladder carcinoma cell line. Cell 29, 161–9.PubMedCrossRefGoogle Scholar
  39. Sinn, E., Muller, W., Pattengale, P., Tepler, I., Wallace, R. and Leder, P., 1987, Coexpression of MMTV/v-Ha-ras and MMTV/c-myc genes in transgenic mice: synergistic action of oncogenes in vivo. Cell 49, 465–475.PubMedCrossRefGoogle Scholar
  40. Slamon, D.J., Clark, G.M., Wong, S.G., Levin, W.J. Ullrich, A., McGuire, W.L., 1987, Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235, 177–182PubMedCrossRefGoogle Scholar
  41. Sonnenberg, A., Daams, H., Calafat, J. and Hilgers, J., 1986a, In vitro differentiation and progression of mouse mammary tumor cells. Cancer Res. 46, 5913–5922.PubMedGoogle Scholar
  42. Sonnenberg, A., Daams, H., van der Valk, M.A., Hilkens, J. and Hilgers, J., 1986b, Development of mouse mammary gland: Identification of stages in differentiation of luminal and myoepithelial cells using monoclonal antibodies and polyvalent antiserum against keratin. J. Histochem. Cytochem. 34, 1037–46.PubMedCrossRefGoogle Scholar
  43. Spandidos, D.A. and Wilkie, N.M., 1984, Malignant transformation of early passage rodent cells by a single mutated human oncogene. Nature 310, 469–475PubMedCrossRefGoogle Scholar
  44. Stewart, T.A., Pattengale, P.K. and Leder, P., 1984, Spontaneous mammary adenocarcinomas in transgenic mice that carry and express MTV/myc fusion genes. Cell 38, 627–637.PubMedCrossRefGoogle Scholar
  45. Varley, J.M., Swallow, J.E., Brammar, W.J., Whittaker, J.L. and Walker, R.A., 1987, Alterations to either c-erbB-2 (neu) or c-myc proto-oncogenes in breast carcinoma correlate with poor short term prognosis. Oncogene 1, 423–430.PubMedGoogle Scholar
  46. Varley, J.M., Walker, R.A., Casey, G. and Brammar, W.J., 1988, A common alteration to the int-2 proto-oncogene in DNA from primary breast carcinomas. Oncogene 3, 87–91.Google Scholar
  47. Wagner, E. F., Vanek, M. and Vennstrom, B., 1985, Transfer of genes into embryonal carcinoma cells by retrovirus infection: efficient expression from an internal promoter. The EMBO J. 4, 663–666.Google Scholar
  48. Zerlin, M., Julius, M.A., Cerni, C. and Marcu, K.B., 1987, Elevated expression of an exogenous c-myc gene is insufficient for transformation and tumorigenic conversion of established fibroblasts. Oncogene 1, 19–28.PubMedGoogle Scholar
  49. Zhou, D.J., Casey, G. and Cline, M.J., 1988, Amplification of human int-2 in breast cancers and squamous carcinomas. Oncogene 2, 279–282.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1989

Authors and Affiliations

  • Walter H. Günzburg
    • 1
  • Brian Salmons
    • 2
  • Robert Ullrich
    • 3
  1. 1.Abteilung für Molekulare ZellpathologieGesellschaft für Strahlen und Umweltforschung mbH (GSF)NeuherbergGermany
  2. 2.Lehrstuhl für Molekulare TierzuchtLudwig-Maximillians UniversitätMünchenGermany
  3. 3.Biology DivisionOak Ridge National LaboratoryOak RidgeUSA

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