Transgenic models of breast cancer metastasis

  • David L. Dankort
  • William J. Muller
Part of the Cancer Treatment and Research book series (CTAR, volume 83)


Traditionally it has been difficult to genetically define the events that lead to the formation of metastatic mammary tumors. While a number of gene products have been implicated in the development of mammary carcinomas, few have been demonstrated to play causative roles in mammary tumor formation. With the advent of transgenic mouse technology, the basic researcher can now target the expression of a gene product to a particular tissue. This has provided scientists with the ability to create mouse models of human diseases. Of particular interest is the generation of transgenic mice carrying genes thought to play important roles in the initiation/progression of mammary carcinomas. From these model systems have emerged murine tumors that not only mimic human pathologies but have the propensity to metastasize to the lung, mirroring one of the major sites of human metastases. Here we review transgenic models of mammary tumorigenesis, with particular emphasis on those that develop metastatic mammary carcinomas.


Transgenic Mouse Mammary Tumor Mammary Epithelium Mammary Tumorigenesis Polyoma Virus 
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  1. 1.
    Dupont WD, Page DL (1985) Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med 312:146–151.PubMedGoogle Scholar
  2. 2.
    Sato T, Tanigami A, Yamakawa K, Akiyama F, Kasumi F, Sakamoto G, Nakamura Y (1990) Allelotype of breast cancer: Cumulative allele losses promote tumor progression in primary breast cancer. Cancer Res 50:7184–7189.PubMedGoogle Scholar
  3. 3.
    Morrison BW (1994) The genetics of breast cancer. Hemotol Oncol Clin North Am 8:15–27,Google Scholar
  4. 4.
    Gasparini G, Bevilacqua, Pozza F, Meli S, Boracchi P, Marubini E, Sainsbury JRC (1992) Value of epidermal growth factor receptor status compared with growth fraction and other factors for prognosis in early breast cancer. Br J Cancer 66:970–976.PubMedGoogle Scholar
  5. 5.
    Sainsbury JRC, Nicholson S, Angus B, Farndon JR, Malcolm AJ, Harris AL (1988) Eidermal growth factor receptor status of histological sub-types of breast cancer. Br J Cancer 58:458–460.PubMedGoogle Scholar
  6. 6.
    Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DË, Levin WJ, Stuart SG, Udove J, Ullrich A, Press MF (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707–712.PubMedGoogle Scholar
  7. 7.
    Zhou DJ, Casey G, Cline MJ (1988) Amplification of human int-2 in breast cancers and squamous carcinomas. Oncogene 2:279–282.PubMedGoogle Scholar
  8. 8.
    Schuuring E, Verhoeven E, van Tinteren H, Peterse JL, Nunnink B, Thunnissen FBJM, Devilee P, Cornelisse CJ, van der Vijver MJ, Mooi WJ (1992) Amplification of genes within the chromosome llql3 region is indicative of poor prognosis in patients with operable breast cancer. Cancer Res 52:5229–5234.PubMedGoogle Scholar
  9. 9.
    Berns EMJJ, Klijn JGM, van Putten WLJ, van Staveren IL, Portengen H, Foekens JA (1992) c-myc amplification is a better prognostic factor than HER2/neu amplification in primary breast cancer. Cancer Res 52:1107–1113.PubMedGoogle Scholar
  10. 10.
    Buckley MF, Sweeney KJE, Hamilton JA, Sini RL, Manning DL, Nicholson RI, deFazio A, Watts CKW, Musgrove EA, Sutherland RL (1993) Expression and amplification of cyclin genes in human breast cancer. Oncogene 8:2127–2133.PubMedGoogle Scholar
  11. 11.
    Bartkova J, Lukas J, Muller H, Lutzhoft D, Strauss M, Bartek J (1994) Cyclin D1 protein expression and function in human breast cancer. Int J Cancer 57:353–361.PubMedGoogle Scholar
  12. 12.
    Ben Cheickh M, Rouanet P, Louason G, Jeanteur P, Theillet C (1992) An attempt to define sets of cooperating genetic alterations in human breast cancer. Int J Cancer 51:542–547.Google Scholar
  13. 13.
    Webster MA, Muller WJ (1994) Mammary tumorigenesis and metastasis in transgenic mice. Semin Cancer Biol 5:69–76.PubMedGoogle Scholar
  14. 14.
    Cardiff RD, Muller WJ (1993) Transgenic mouse models of mammary tumorigenesis. Cancer Surv 16:97–113.PubMedGoogle Scholar
  15. 15.
    Andres A-C, Schonenberger C-A, Groner B, Henninghausen L, LeMeur M, Gerlinger P (1987) Ha-ras oncogene expression directed by a milk gene promoter; tissue specificity, hormonal regulation, and tumor induction in transgenic mice. Proc Natl Acad Sci USA 84:1299–1303.PubMedGoogle Scholar
  16. 16.
    Andres A-C, van der Valk MA, Schonenberger C-A, Fluckiger F, LeMeur M, Gerlinger P, Groner B (1988) Ha-ras and c-myc oncogene expression interferes with morphological and functional differentiation of mammary epithelial cells in single and double transgenic mice. Genes Dev 2:1486–1495.PubMedGoogle Scholar
  17. 17.
    Schoonenberger C-A, Andres A-C, Groner B, van der Aalk M, LeMeur M, Gerlinger P (1988) Targeted c-myc expression in mammary glands of transgenic mice induces mammary tumors with constitutive milk protein gene transcription. EMBO J 7:169–175.Google Scholar
  18. 18.
    Pattengale PK, Stewart TA, Leder A, Sinn E, Muller W, Tepler I, Schmidt E, Leder P (1989) Animal models of human disease: Pathology and molecular biology of spontaneous neoplasms occurring in transgenic carrying and expressing activated cellular oncogenes. Am J Pathol 135:39–61.PubMedGoogle Scholar
  19. 19.
    Casey G, Smith R, McGillivray D, Peters G, Dickson C (1986) Characterization and chromosome assignment of the human homolog of int-2, a potential proto-oncogene. Mol Cell Biol 6:502–510.PubMedGoogle Scholar
  20. 20.
    Lammie GA, Peters G (1991) Chromosome 11q13 abnormalities in human cancer. Cancer Cells 3:413–420.PubMedGoogle Scholar
  21. 21.
    Schuuring E, Verhoeven E, Litvinov S, Michalides RJAM (1993) The product of the EMS1 gene, amplified and overexpressed in human carcinomas, is homologous to a v-src substrate and is located in cell-substratum contact sites. Mol Cell Biol 13:2891–2898.PubMedGoogle Scholar
  22. 22.
    Muller WJ, Lee FS, Dickson C, Peters G, Pattengale P, Leder P (1990) The int-2 gene product acts as an epithelial growth factor in transgenic mice. EMBO J 9:907–913.PubMedGoogle Scholar
  23. 23.
    Ornitz DM, Moreadith RW, Leder P (1991) Binary system for regulating transgene expression in mice: Targeting int-2 expression with yeast GAL4/UAS control elements. Proc Natl Acad Sci USA 88:698–702.PubMedGoogle Scholar
  24. 24.
    Wang TC, Cardiff RD, Zukerberg L, Lees E, Arnold A, Schmidt EV (1994) Mammary hyperplasia and carcinoma in MMTV/cyclin D1 transgenic mice. Nature 369:669–671.PubMedGoogle Scholar
  25. 25.
    Land H, Parada LF, Weinberg RA (1983) Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature 304:596–602.PubMedGoogle Scholar
  26. 26.
    Weinberg RA (1985) The action of oncogenes in the cytoplasm and the nucleus. Science 230:770–776.PubMedGoogle Scholar
  27. 27.
    Weinberg RA (1989) Oncogenes and multistep carcinogenesis. In Oncogenes and the Molecular Origins of Cancer. RA Weinberg (ed). Cold Spring Harbor, NY: Cold Spring Harbor Laboratory, pp 307–326.Google Scholar
  28. 28.
    Stewart TA, Pattengale PK, Leder P (1984) Spontaneous mammary adenocarcinomas in transgenic mice that carry and express MTV/myc fusion genes. Cell 38:627–637.PubMedGoogle Scholar
  29. 29.
    Sinn E, Muller W, Pattengale P, Tepler I, Wallace R, Leder P (1987) Coexpression of MMTV/v-Ha-ras and MMTV-c-myc genes in transgenic mice: Synexgistc action of oncogenes in vivo. Cell 49:465–475.PubMedGoogle Scholar
  30. 30.
    Leder A, Pattengale PK, Kuo A, Stewart TA, Leder P (1986) Consequences of widespread deregulation of the c-myc gene in transgenic mice: Multiple neoplasms and normal development. Cell 45:485–495.PubMedGoogle Scholar
  31. 31.
    Tremblay PJ, Pothier F, Hoang T, Trembley G, Brownstein S, Liszaur A, Jolicoeur P (1989) Transgenic mice carrying the mouse mammary tumor virus ras fusion gene: Distinct effects in various tissues. Mol Cell Biol 9:854–859.PubMedGoogle Scholar
  32. 32.
    Yoshida T, Miyagawa K, Odagiri H, Sakamoto H, Little PFR, Terada M, Sugimura T (1987) Genomic sequences of hst, a transforming gene encoding a protein homologous to fibroblast growth factors and the int-2-encoded protein. Proc Natl Acad Sci USA 84:7305–7309.PubMedGoogle Scholar
  33. 33.
    Nusse R, Varmus HE (1992) Wnt genes. Cell 69:1073–1088.PubMedGoogle Scholar
  34. 34.
    Pathak VK, Strange R, Young LJT, Morris DW, Cardiff RD (1987) Survey of int region DNA rearrangements in 3 and BALB/cfCH3 mouse mammary tumor system. J Natl Cancer Inst 78:327–331.PubMedGoogle Scholar
  35. 35.
    Gray DA, Jackson DP, Percy DH, Morris VL (1986) Activation of int-1 and int-2 loci in GRf mammary tumors. Virology 154:271–278.PubMedGoogle Scholar
  36. 36.
    Peters G, Lee AE, Dickson C (1989) Concerted activation of two potential proto-oncogenes in carcinomas induced by mouse mammary tumour virus. Nature 320:628–631.Google Scholar
  37. 37.
    Tsukamoto AS, Grosschedi R, Guzman RC, Parslow T, Varmus HE (1988) Expression of the int-1 gene in transgenic mice is associated with mammary gland hyperplasia and adenocarcinomas in male and female mice. Cell 55:619–625.PubMedGoogle Scholar
  38. 38.
    Medina D (1982) Mammary tumors. In The Mouse in Biomedical Research. HL Foster, JD Small, JG Fox (eds). New York: Academic Press, pp 373–396.Google Scholar
  39. 39.
    Kwan H, Pecenka V, Tsukamoto A, Parslow TG, Guzman R, Lin T-P, Muller WJ, Lee FS, Leder P, Varmus HE (1992) Transgenes expressing the WntI-1 and int-2 proto-oncogenes cooperate during mammary carcinogenesis in doubly transgenic mice. Mol Cell Biol 12:147–154.PubMedGoogle Scholar
  40. 40.
    Padhy LC, Shih C, Cowing D, Finkelstein R, Weinberg RA (1982) Identification of a phosphoprotein specifically induced by the transforming DNA of rat neuroblastomas. Cell 28:865–871.PubMedGoogle Scholar
  41. 41.
    Bargmann CI, Hung M-C, Weinberg RA (1986) The neu oncogene encodes an epidermal growth factor receptor-related protein. Nature 319:226–230.PubMedGoogle Scholar
  42. 42.
    Coussens L, Yang-Feng TL, Liao Y-C, Chen E, Gray A, McGrath J, Seeburg PH, Libermann TA, Schlessinger J, Francke U, Levinson A, Ullrich A (1985) Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosome location with neu oncogene. Science 230:1132–1139.PubMedGoogle Scholar
  43. 43.
    Yamamoto T, Ikawa S, Akiyama T, Semba K, Nomura N, Miyajima N, Saito T, Toyoshima K (1986) Similarity of protein encoded by the human c-erb-B-2 gene to the epidermal growth factor receptor. Nature 319:230–234.PubMedGoogle Scholar
  44. 44.
    Bargmann CI, Hung M-C, Weinberg RA (1986) Multiple independent activations of the neu oncogene by a point mutation altering the transmembrane domain of pl85. Cell 45:649–657.PubMedGoogle Scholar
  45. 45.
    Bargmann CI, Weinberg RA (1988) Increased tyrosine kinase activity associated with the protein encoded by the activated neu oncogene. Proc Natl Acad Sci USA 85:5394–5398.PubMedGoogle Scholar
  46. 46.
    Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: Correlation of relapse and survival with the amplification of the HER-2/neu oncogene. Science 235:177–182.PubMedGoogle Scholar
  47. 47.
    van de Vijver MJ, Peterse JL, Mooi WJ, Wisman P, Lomans J, Dalesio O, Nusse R (1988) Neu overexpression in breast cancer. N Engl J Med 319:1239–1245.PubMedGoogle Scholar
  48. 48.
    King C, Kraus MH, Aaronson SA (1985) Amplification of a novel v-erbB-related gene in a human mammary carcinoma. Science 229:974–976.PubMedGoogle Scholar
  49. 49.
    Mansour EG, Ravdin PM, Dressler L (1994) Prognostic factors in early breast carcinoma. Cancer 74:381–400.PubMedGoogle Scholar
  50. 50.
    Hynes NE, Stern DF (1994) The biology of erbB-2/neu/HER-2 and its role in cancer. Biochim Biophys Acta 1198:165–184.PubMedGoogle Scholar
  51. 51.
    Gullick WJ, Love SB, Wright C, Barnes DM, Gusterson B, Harris AL, Altman DG (1991) C-erbB-2 protein overexpression in breast cancer is a risk factor in patients with involved and uninvolved lymph nodes. Br J Cancer 63:434–438.PubMedGoogle Scholar
  52. 52.
    Patterson MC, Dietrich KD, Danyluk J, Paterson AH, Lees AW, Jamil N, Hanson J, Jenkins H, Krause BE, McBlain WA, Slamon DJ, Fourney RM (1991) Correlation between c-erbB2 amplification and risk of recurrent disease in node-negative breast cancer. Cancer Res 51:556–567.Google Scholar
  53. 53.
    Tripathy D, Benz C (1994) Growth factors and their receptors. Hematol Oncol Clin North Am 8:29–50.PubMedGoogle Scholar
  54. 54.
    Muller WJ, Sinn E, Pattengale PK, Wallace R, Leder P (1988) Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. Cell 54:105–115.PubMedGoogle Scholar
  55. 55.
    Bouchard L, Lamarre L, Trembley PJ, Jolicoeur P (1989) Stochastic appearance of mammary tumors in transgenic mice carrying the c-neu oncogene. Cell 57:931–936.PubMedGoogle Scholar
  56. 56.
    Guy CT, Webster MA, Schaller M, Parsons TJ, Cardiff RA, Muller WJ (1992) Expression of the neu protooncogene in the mammary epithlium of transgenic mice induces metastatic disease. Proc Natl Acad Sci USA 89:10578–10582.PubMedGoogle Scholar
  57. 57.
    Siegel PM, Dankort DL, Hardy WR, Muller WJ (1994) Novel activating mutations in the neu proto-oncogene involved in induction of mammary tumors. Mol Cell Biol 14:7068–7077.PubMedGoogle Scholar
  58. 58.
    Kaplan DR, Pallas DC, Morgan B, Schaffhausen B, Roberts TM (1988) Mechanisms of transformation by polyoma middle T antigen. Biochim Biophys Acta 948:345–364.Google Scholar
  59. 59.
    Berebbi M, Martin PM, Berthois Y, Bernard AM, Blangy D (1990) Estradiol dependence of the specific mammary tissue targetting of polyoma virus oncogenicity in nude mice, Oncogene 5:505–509.PubMedGoogle Scholar
  60. 60.
    Israel MA, Chan HW, Hourihan SA, Rowe WP, Martin MA (1979) Biological activity of polyoma viral DNA in mice and hamsters. J Virol 29:990–996.PubMedGoogle Scholar
  61. 61.
    Treisman R, Novak U, Favaloro J, Kamen R (1981) Transformation of rat cells by an altered polyoma virus genome expressing only the middle T protein. Nature 292:595–600.PubMedGoogle Scholar
  62. 62.
    Charmichel G, Schaffhausen BS, Mandel G, Liang TJ, Benjamin TL (1984) Transformation by polyoma virus is drastically reduced substitution of phenylalanine for tyrosine at residue 315 of middle-sized tumor antigen. Proc Natl Acad Sci USA 81:679–683.Google Scholar
  63. 63.
    Markland W, Oostra BA, Harvey R, Markham AF, Colledge WH, Smith AE (1986) Site directed mutagenesis of Polyomavirus middle-T antigen sequence encoding tyrosine 315 and tyrosine 250. J Virol 59:384–391.PubMedGoogle Scholar
  64. 64.
    Druker BJ, Sibert L, Roberts TM (1992) Polyomavirus middle T-antigen NPTY mutants. J Virol 66:5770–5776.PubMedGoogle Scholar
  65. 65.
    Campbell KS, Ogris E, Burke B, Su W, Auger KR, Druker BJ, Schaffhausen BS, Roberts TM, Pallas DC (1994) Polyoma middle tumor antigen interacts with SHC protein via the NPTY (Ans-Pro-Thr-Tyr) motif in middle tumor antigen. Proc Natl Acad Sci USA 91:6344–6348.PubMedGoogle Scholar
  66. 66.
    Dilworth SM, Brewster CEP, Jones MD, Lanfrancone L, Pelicci G, Pelicci PG (1994) Transformation by polyoma middle T-antigen involves the binding and tyrosine phosphorylation of Shc. Nature 367:87–90.PubMedGoogle Scholar
  67. 67.
    Markland W, Smith AE (1987) Mutants of Polyomavirus middle-T antigen. Biochim Biophys Acta 907:299–321.PubMedGoogle Scholar
  68. 68.
    Guy CT, Cardiff RA, Muller WJ (1992) Induction of mammary tumors by expression of Polyomavirus middle T oncogene: A transgenic mouse model for metastatic disease. Mol Cell Biol 12:954–961.PubMedGoogle Scholar
  69. 69.
    Folkman J (1992) The role of angiogenesis in tumor growth. Semin Cancer Biol 3:65–71.PubMedGoogle Scholar
  70. 70.
    Srivastava A, Laidler P, Davies RP, Horgan K, Hughes LE (1988) The prognostic significance of tumor vascularity in intermediate-thickness (0.76–4.0 mm thick) skin melanoma. Am J Pathol 133:419–423.PubMedGoogle Scholar
  71. 71.
    Weidner N, Semple JP, Welch WR, Folkman J (1991) Tumor angiogenesis and metastasis — correlation in invasive breast carcinoma. N Engl J Med 324:1–8.PubMedGoogle Scholar
  72. 72.
    Folkman J, Watson K, Ingber D, Hanahan D (1989) Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 339:58–61.PubMedGoogle Scholar
  73. 73.
    Folkman J, Klagsbrun M (1987) Angiogenic factors. Science 235:442–447.PubMedGoogle Scholar
  74. 74.
    Aznavoorian S, Murphy AN, Stetler-Stevenson WG, Liotta LA (1993) Molecular aspects of tumor cell invasion and metastasis. Cancer 71:1368–1382.PubMedGoogle Scholar
  75. 75.
    Williams RL, Courtneidge SA, Wagner EF (1988) Embryonic lethalities and endothelial tumors in chimeric mice expressing the polyoma virus middle T oncogene. Cell 52:121–131.PubMedGoogle Scholar
  76. 76.
    Williams RL, Risau W, Zerwes H-G, Drexler H, Aguzzi A, Wagner EF (1989) Endothelioma cells expressing the polyoma middle T oncogene induce hemangiomas by host cell recruitment. Cell 57:1053–1063.PubMedGoogle Scholar
  77. 77.
    Montesano R, Pepper MS, Mohle-Steinlein U, Risau W, Wagner EF, Orci L (1990) Increased proteolytic activity is responsible for abberant behaviour of endothelial cells expressing the middle T oncogene. Cell 62:436–445.Google Scholar
  78. 78.
    Courtneidge SA, Smith AE (1983) Polyoma transforming protein associates with the product of the c-src cellular gene. Nature 303:435–439.PubMedGoogle Scholar
  79. 79.
    Muthuswamy SK, Siegel PS, Dankort DL, Webster MA, Muller WJ (1994) Mammary tumors expressing the neu proto-oncogene possess elevated c-Src tyrosine kinase activity, Mol Cell Biol 14:735–743.PubMedGoogle Scholar
  80. 80.
    Lutrell DK, Lee A, Lansing TJ, Crosby RM, Jung KD, Willard D, Luther M, Rodriguez M, Berman J, Gilmer TM (1994) Involvement of pp60c-src with two major signaling pathways in human breast cancer. Proc Natl Acad Sci USA 91:83–97.Google Scholar
  81. 81.
    Soriano P, Montgomery C, Geske R, Bradley A (1991) Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell 64:693–702.PubMedGoogle Scholar
  82. 82.
    Stein PL, Vogel H, Soriano P (1994) Combined deficiences of Src, Fyn and Yes tyrosine kinases in mutant mice. Genes Dev 8:1999–2007.PubMedGoogle Scholar
  83. 83.
    Guy CT, Muthuswamy SK, Cardiff RA, Sariano P, Muller WJ (1994) Activation of the c-Src tyrosine kinase is required for the induction of mammary tumors in transgenic mice. Genes Dev 8:23–32.PubMedGoogle Scholar
  84. 84.
    Thomas JE, A. A, Soriano P, Wagner EF, Brugge J (1993) Induction of tumor formation and cell transformation by polyoma middle T antigen in the absence of src. Oncogene 8:2521–2526.PubMedGoogle Scholar
  85. 85.
    Kiefer F, Anhauser I, Soriano P, Aguzzi A, Courtneidge, Wagner EF (1994) Endothelial cell transformation by Polyomavirus middle T antigen in mice lacking Src-related kinases. Curr Biol 4:100–109.PubMedGoogle Scholar
  86. 86.
    Xin JH, Cowie A, Lachance P, Hassell JA (1992) Molecular cloning and characterization of PEA3, a new member of the Ets oncogene family that is differentially expressed in mouse embryonic cells. Genes Dev 6:481–496.PubMedGoogle Scholar
  87. 87.
    Trimble MS, Xin J-H, Guy CT, Muller WJ, Hassell JA (1993) PEA3 is overexpressed in mouse metastatic mammary adenocarcinomas. Oncogene 8:3037–3042.PubMedGoogle Scholar
  88. 88.
    Wasylyk C, Flores P, Gutman A, Wasylyk B (1989) PEA3 is a nuclear target for transcription activation by non-nuclear oncogenes. EMBO J 8:3371–3378.PubMedGoogle Scholar
  89. 89.
    Wasylyk C, Gutman A, Nicholson R, Wasylyk B (1991) The c-Ets oncoprotein activates the stromelysin promoter through the same elements as several non-nuclear oncoproteins. EMBO J 10:1127–1134.PubMedGoogle Scholar
  90. 90.
    McDonnell SE, Kerr LD, Matrisian LM (1990) Epidermal growth factor stimulation of stromelysin mRNA in rat fibroblasts requires induction of proto-oncogene c-fos and c-jun and activation of protein kinase C. Mol Cell Biol 10:4284–4293.PubMedGoogle Scholar
  91. 91.
    Edwards DR, Rocheleau H, Sharma RR, Wills AJ, Cowie A, Hassell JA, Heath JK (1992) Involvement of API and PEA3 binding sites in the regulation of murine tissue inhibitor of metalloproteinases-1 (TIMP-1) transcription. Biochim Biophys Acta 1171:41–55.PubMedGoogle Scholar
  92. 92.
    Nielsen LL, Discafani CM, Gurnani M, Tyler RD (1991) Histopathology of salivary and mammary gland tumors in transgenic mice expressing a human Ha-ras oncogene. Cancer Res 51:3762–3767.PubMedGoogle Scholar
  93. 93.
    Stein D, Wu J, Fuqua SA, Roonprapunt C, Yajnik V, D’Eustachio P, Moskow JJ, Buchberg AM, Osborne CK, Margolis B (1994) The SH2 domain protein GRB7 is co-amplified, overexpressed and in a tight complex with HER2 in breast cancer. EMBO J 13:1331–1340.PubMedGoogle Scholar
  94. 94.
    Peles E, Ben Levy R, Or E, Ullrich A, Yarden Y (1991) Oncogenic forms of the neu/HER2 tyrosine kinase are permanently coupled to phospholipase Cg. EMBO J 10:2077–2086.PubMedGoogle Scholar
  95. 95.
    Segatto O, Pelicci G, Giuli S, Digeiesi G, Di Fiore PP, McGlade J, Pawson T, Pelicci PG (1993) Shc products are substrates of erbB-2 kinase. Oncogene 8:2105–2112.PubMedGoogle Scholar
  96. 96.
    Scott GK, Dodson JM, Montgomery PA, Johnson RM, Sarup JC, Wong WL, Ullrich A, Shepard HM, Benz CC (1991) pl85HER2 signal transduction in breast cancer cells. J Biol Chem 266:14300–14305.PubMedGoogle Scholar
  97. 97.
    Peles E, Lamprecht R, Ben-Levy R, Tzahar E, Yarden Y (1992) Regulated coupling or the Neu receptor to phosphoinositol 3′-kinase and its release by oncogenic activation. J Biol Chem 267:12266–12274. PubMedGoogle Scholar
  98. 98.
    Ojan X, Dougall WC, Fei Z, Greene MI (1995) Intermolecular association and transphosphorylation of different neu-kinase forms permit SH2-dependent signaling and oncogenic transformation. Oncogene 10:211–219.Google Scholar
  99. 99.
    Vogel W, Lammers R, Huang J, Ullrich A (1993) Activation of a phosphotyrosine phosphatase by tyrosine phosphorylation. Science 259:1611–1614.PubMedGoogle Scholar
  100. 100.
    Li N, Batzer A, Daly R, Yajnik V, Skolnik E, Chardin P, Bar-Sagi D, Margolis B, Schlessinger J (1993) Guanine-nucleotide-releasing factor hSOS1 binds to GRB2 and links receptor tyrosine kinases to ras signalling. Nature 363:85–88.PubMedGoogle Scholar
  101. 101.
    Rozakis-Adcock M, Fernley R, Wade J, Pawson T, Bowtell D (1993) The SH2 and SH3 domains of mammalian GRB2 couple the EGF receptor to the ras activator mSOS1. Nature 363:83–85.PubMedGoogle Scholar
  102. 102.
    Egan SE, Giddings BW, Brooks MW, Buday L, Sizeland AM, Weinberg RA (1993) Association of SOS ras exchange protein with GRB2 is implicated in tyrosine kinase signal transduction and transformation. Nature 360:45–51.Google Scholar
  103. 103.
    Buday L, Downward J (1993) Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and SOS nucleotide exchange factor. Cell 73:611–620.PubMedGoogle Scholar
  104. 104.
    Courtneidge SA, Hebner A (1987) An 81 kDa protein complexed with middle T antigen and pp60c-src: A possible phosphatidylinositol kinase. Cell 50:1031–1037.PubMedGoogle Scholar
  105. 105.
    Whitman M, Kaplan DR, Schaffhausen B, Cantley LT, Roberts TM (1985) Association of phosphatidylinositol kinase activity with polyoma middle T competent for transformation. Nature 315:239–242.PubMedGoogle Scholar
  106. 106.
    Bolen JB, Theile CJ, Israel MA, Yonemoto W, Lipsich LA, Brugge JS (1988) Enhancement of cellular src gene product-associated tyrosine kinase activity following Polyomavirus infection and transformation. Cell 38:161–111. Google Scholar
  107. 107.
    Kornbluth S, Sueul M, Hanafusa H (1986) Association of the Polyomavirus middle T antigen with the c-yes protein. Nature 325:171–173.Google Scholar
  108. 108.
    Kypta RM, Hemming A, Courtneidge SA (1988) Identification and characterization of p59 fyn (a Src like protein kinase) in normal and Polyomavirus transformed cells, EMBO J 7:3837–3844.PubMedGoogle Scholar
  109. 109.
    Cheng SH, Harvey R, Espino PC, Semba K, Yamanota T, Toyoshima K, Smith AE (1988) Peptide antibodies to the human pp59 c-fyn are capable of complex formation with the middle-T antigen of Polyomavirus. EMBO J 7:3845–3855.PubMedGoogle Scholar
  110. 110.
    Pallas DC, Shahtik LK, Martin BL, Jasper S, Miller TB, Brautigan DL, Roberts TM (1990) Polyoma small and middle T antigens and SV40 small t antigen form stable complexes with protein phosphatase 2A. Cell 60:167–176.PubMedGoogle Scholar
  111. 111.
    Walter GRR, Slaughter C, Mumby M (1990) Association of protein phosphatase 2A with polyoma virus medium tumor antigen. Proc Natl Acad Sci USA 87:2521–2521.PubMedGoogle Scholar
  112. 112.
    Moodie SA, Wolfman A (1994) The 3Rs of life: ras, raf, and growth regulation. Trends Biol Sci 10:44–48.Google Scholar
  113. 113.
    Marshall CJ (1994) MAP kinase kinase kinase, MAP kinase kinase, and MAP kinase. Curr Opin Gen Dev 4:82–89.Google Scholar
  114. 114.
    Daum G, Eisenmann-Tappe I, Fries H-W, Troppmair J, Rapp UR (1994) The ins and outs of raf kinases. Trends Biol Sci 19:474–480.Google Scholar
  115. 115.
    Karin M (1994) Signal transduction from the cell surface to the nucleus through the phosphorylation of transcription factors. Curr Opin Cell Biol 6:415–424.PubMedGoogle Scholar
  116. 116.
    Hill CS, Treisman R (1995) Transcriptional regulation by extracellular signals: Mechanisms and specificity. Cell 80:199–211.PubMedGoogle Scholar

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© Kluwer Academic Publishers 1996

Authors and Affiliations

  • David L. Dankort
  • William J. Muller

There are no affiliations available

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