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Transgenic and gene knockout mice in cancer research


Transgenic animal technology, and the use of germline manipulation for the creation of targeted gene mutations, has resulted in a plethora of murine models for cancer research. Our understanding of some of the important issues regarding the mechanisms controlling cell division, differentiation and death has dramatically advanced in recent years through exploitation of these techniques to generate transgenic mice. In particular, the generation of mice with targeted mutations in genes encoding proteins of oncological interest has proved to be a useful way of elucidating the function of these gene productsin vivo. Transgenic mouse models have provided some insight into the complex oncogenic events contributing to cellular dysregulation and the loss of growth control that can lead to tumorigenesis. These animal studies have highlighted the fact that there are many different stages at which the loss of cell cycle control can occur, as a result of mutations affecting proteins anywhere from the cell surface to the nucleus. Although mutations affecting growth factors, growth factor receptors, signal transduction molecules, cytoplasmic proteins or nuclear proteins might appear to be very distinct, the end result of these changes may be accelerated and unchecked cell growth ultimately leading to cancer. It is beyond the scope of this review to mention every animal model that has been developed for cancer research, especially since many of the early studies have been covered extensively in previous reviews. This article will instead focus on a small selection of transgenic and knockout animal models which exemplify how proteins from distinct localisations along multiple pathways can contribute to loss of cell cycle control and the pathogenesis of cancer.

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  1. 1.

    Adams JM, Cory S: Transgenic models of tumor development. Science 254: 1161–1167, 1991

  2. 2.

    Aaronson SA: Growth factors and cancer. Science 254: 1146–1153, 1991

  3. 3.

    Weinberg RA: Tumor suppressor genes. Science 254: 1138–1146, 1991

  4. 4.

    Merlino G: Regulatory imbalances in cell proliferation and cell death during oncogenesis in transgenic mice. Semin Cancer Biol 5: 13–20, 1994

  5. 5.

    Matzuk MM, Bradley A: Identification and analysis of tumor suppressor genes using transgenic mouse models. Semin Cancer Biol 5: 37–45, 1994

  6. 6.

    Christofori G, Hanahan D: Molecular dissection of multistage tumorigenesis in transgenic mice. Semin Cancer Biol 5: 3–12, 1994

  7. 7.

    Salomon DS, Kim N, Saeki T, Ciardiello F: Transforming growth factor α: an oncodevelopmental growth factor. Cancer Cells 2: 389–397, 1990

  8. 8.

    Derynck R, Goeddel DV, Ullrich A, Gutterman JU, Williams RD, Bringham TS, Berger WH: Synthesis of mRNAs for transforming growth factors α and β and the epidermal growth factor receptor by human tumors. Cancer Res 47: 707–712, 1987

  9. 9.

    Jhappan C, Stahle C, Harkins RN, Fausto N, Smith GH, Merlino GT: TGFα overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas. Cell 61: 1137–1146, 1990

  10. 10.

    Sandgren EP, Luetteke NC, Palmiter RD, Brinster RL, Lee DC: Overexpression of TGFα in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia and carcinoma of the breast. Cell 61: 1121–1135, 1990

  11. 11.

    Matsui Y, Halter SA, Holt JT, Hogan BLM, Coffey RJ: Development of mammary hyperplasia and neoplasia in MMTV-TGFα transgenic mice. Cell 61: 1147–1155, 1990

  12. 12.

    Sandgren EP, Luetteke NC, Qui TH, Palmiter RD, Brinster RL, Lee DC: Transforming growth factor α dramatically enhances oncogene-induced carcinogenesis in transgenic mouse pancreas and liver. Mol Cell Biol 13: 320–330, 1993

  13. 13.

    Jhappan C, Takayama H, Dickson RB, Merlino G: Transgenic mice provide genetic evidence that transforming growth factor a promotes skin tumorigenesis via h-ras-de-pendent and h-ras-independent pathways. Cell Growth and Differentiation 5: 385–394, 1994

  14. 14.

    Coffey RJ, Meise KS, Matsui Y, Hogan BL, Dempsey PJ, Halter SA: Acceleration of mammary neoplasia in transforming growth factor alpha transgenic mice by 7,12-di-methylbenzanthracene. Cancer Res 54: 1678–1683, 1994

  15. 15.

    Rogler CE, Yang D, Rossetti L, Donohoe J, Alt E, Chang CJ, Rosenfeld R, Neely K, Hintz R: Altered body composition and increased frequency of diverse malignancies in in-sulin-like growth factor-II transgenic mice. J Biol Chem 269: 13779–13784, 1994

  16. 16.

    Renauld JC, van der Lugt N, Vink A, van Roon M, Godfraind C, Warnier G, Merz H, Feller A, Berns A, van Snick J: Thymic lymphomas in interleukin-9 transgenic mice. Oncogene 9: 1327–1332, 1994

  17. 17.

    Muller WJ, Sinn E, Pattengale PK, Wallace R, Leder P: Single step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. Cell 54: 105–115, 1988

  18. 18.

    Bouchard L, Lamarre L, Tremblay PJ, Jolicoeur P: Stochastic appearance of mammary tumors in transgenic mice carrying the MMTV/c-neu oncogene. Cell 57: 931–936, 1989

  19. 19.

    Muthaswamy SK, Siegel PM, Dankort DL, Webster MA, Muller WJ: Mammary tumors expressing theneu protooncogene possess elevated c-Src tyrosine kinase activity. Mol Cell Biol 14: 735–743, 1994

  20. 20.

    Jhappan C, Geiser AG, Kordon EC, Bagheri D, Hennighausen L, Roberts AB, Smith GH, Merlino G: Targeting expression of a transforming growth factor beta 1 transgene to the pregnant mammary gland inhibits alveolar development and lactation. EMBO J 12: 1835–1845, 1993

  21. 21.

    Pierce DF, Johnson MD, Matsui Y, Robinson SD, Gold LI, Purchio AF, Daniel CW, Hogan BL, Moses HL: Inhibition of mammary duct development but not alveolar outgrowth during pregnancy in transgenic mice expressing active TGF beta 1. Genes Dev 7: 2308–2317, 1993

  22. 22.

    Glick AB, Kulkarni AB, Tennenbaum T, Hennings H, Flanders KC, O'Reilly M, Sporn MB, Karlsson S, Yuspa SH: Loss of expression of transforming growth factor beta in skin and skin tumors is associated with hyperproliferation and a high risk for malignant conversion. Proc Natl Acad Sci USA 90: 6076–6080, 1993

  23. 23.

    Egan SE, Giddings BW, Brooks MW, Buday L, Sizeland AM, Weinberg RA: Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation. Nature 363: 45–51, 1993

  24. 24.

    Rozakis-Adcock M, Fernly R, Wade J, Pawson T, Bowtell D: The SH2 and SH3 domains of mammalian Grb2 couple the EGF receptor to the Ras activator mSos1. Nature 363: 83–85, 1993

  25. 25.

    Li N, Batzer A, Daly R, Yajnik V, Skolnik E, Chardin P, Bar-Sagi D, Margolis B, Schlessinger J: Guanine-nucleotide-re-leasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling. Nature 363: 85–88, 1993

  26. 26.

    Buday L, Downward J: Epidermal growth factor regulates p21ras through the formation of a complex ofreceptor, Grb2 adapter protein, and Sos nucleotide exchange factor. Cell 73: 611–620, 1993

  27. 27.

    Sinn E, Muller W, Pattengale P, Tepler I, Wallace R, Leder P: Coexpression of MMTV/v-H-ras and MMTV/c-myc genes in transgenic mice: synergistic action of oncogenesin vivo. Cell 49: 465–475, 1987

  28. 28.

    Bailleul B, Surani AM, White S, Bartton S, Brown K, Blessing M, Jorcano J, Balmain A: Skin hyperkeratosis and papilloma formation in transgenic mice expressing aras oncogene from a suprabasal keratin promoter. Cell 62: 697–708, 1990

  29. 29.

    Leder A, Kuo A, Cardiff RD, Sinn E, Leder P: v-H-ras transgene abrogates the initiation step in mouse skin tumorigenesis. Proc Natl Acad Sci USA 87: 9178–9182, 1990

  30. 30.

    Greenlagh DA, Rothnagel JA, Quintanilla MI, Orengo CC, Gagne TA, Bundman DS, Longley MA, Roop DR: Induction of epidermal hyperplasia, hyperkeratosis and papillomas in transgenic mice by a targeted v-ha-ras oncogene. Molec Carcinogenesis 7: 99–110, 1993

  31. 31.

    Sandgren EP, Quaife CJ, Pinkert CA, Palmiter RD, Brinster RL: Oncogene induced liver neoplasia in transgenic mice. Oncogene 4: 715–724, 1989

  32. 32.

    Heisterkamp N, Jenster G, ten Hoeve J, Zovich D, Pattengale PK, Groffen J: Acute leukemia inbcr/abl transgenic mice. Nature 344: 251–253, 1990

  33. 33.

    Tybulewicz VLJ, Crawford CE, Jackson PK, Bronson RT, Mulligan RC: Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl protooncogene. Cell 65: 1153–1163, 1991

  34. 34.

    Schwartzenberg PL, Stall AM, Hardin JD, Bowdish KS, Humaran T, Boast S, Harbison ML, Robertson EJ, Goff SP: Mice homozygous for theabl mutation show poor viability and depletion of selected B and T cell populations. Cell 65: 1165–1175, 1991

  35. 35.

    Laird PW, van der Lugt NM, Clarke A, Domen J, Linders K, McWhir J, Berns A, Hooper M:In vivo analysis of Pim-1 deficiency. Nucleic Acid Res 21: 4750–4755, 1993

  36. 36.

    Domen J, van der Lugt NM, Acton D, Laird PW, Linders K, Berns A: Pim-1 levels determine the size of the early B lymphoid compartments in bone marrow. J Exp Med 178: 1665–1673, 1993

  37. 37.

    McDonnell TJ, Deane N, Platt FM, Nunez G, Jaeger U, McKearn JP, Korsmeyer SJ: Bcl2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell 57: 79–88, 1989

  38. 38.

    McDonnell TJ, Nunez G, Platt FM, Hockenberry D, London L, McKearn JP, Korsmeyer SJ: Deregulated Bcl2-immunoglobulin transgene expands a resting but responsive immunoglobulin M and D expression B cell population. Mol Cell Biol 10: 1901–1907, 1990

  39. 39.

    McDonnell TJ, Korsmeyer SJ: Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14;18). Nature 349: 254–256, 1991

  40. 40.

    Strasser A, Harris AW, Bath ML, Cory S: Novel primitive lymphoid tumors induced in transgenic mice by cooperation betweenmyc andbcl2. Nature 348: 331–333, 1990

  41. 41.

    Katsumata M, Siegel RM, Louie DC, Miyashita T, Tsujimoto Y, Nowell PC, Greene MI, Reed JC: Differential effects of Bcl2 on T and B cells in transgenic mice. Proc Natl Acad Sci USA 89: 11376–11380, 1992

  42. 42.

    Strasser A, Harris AW, Cory S: Bcl2 transgene inhibits T cell death and perturbs thymic self-censorship. Cell 67: 889–899, 1991

  43. 43.

    Sentman CL, Shutter JR, Hockenbery D, Kanagawa O, Korsmeyer SJ: Bcl2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell 67: 879–888, 1991

  44. 44.

    Nakayama KI, Nakayama K, Negishi I, Kuida K, Shinkai Y, Louie MC, Fields LE, Lucas PJ, Stewart V, Alt FW, Loh DY: Disappearance of the lymphoid system in Bcl2 homozygous mutant chimaeric mice. Science 261: 1584–1588, 1993

  45. 45.

    Marx J: New tumor suppressor may rival p53. Science 264: 344–345, 1994

  46. 46.

    White E: p53, guardian of Rb. Nature 371: 21–22, 1994

  47. 47.

    Peters G: Stifled by inhibitions. Nature 371: 204–205, 1994

  48. 48.

    Morgenbesser SD, DePinho RA: Use of transgenic mice to studymyc family gene function in normal mammalian development and in cancer. Semin Cancer Biol 5: 21–36, 1994

  49. 49.

    Stewart TA, Pattengale PK, Leder P: Spontaneous mammary adenicarconomas in transgenic mice that carry and express MTV/myc fusion genes. Cell 38: 627–637, 1984

  50. 50.

    Schoenberger CA, Andres AC, Groner B, van der Valk M, LeMeur M, Gerlinger P: Targeted c-myc gene expression in mammary glands of transgenic mice induces mammary tumors with constitutive milk protein gene transcription. EMBO J 7: 169–175, 1988

  51. 51.

    Adams JM, Harris AW, Pinkert CA, Corcoran LM, Alexander WS, Cory S, Palmiter RD, Brinster RL: Thec-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318: 533–538, 1985

  52. 52.

    Langdon WY, Harris AW, Cory S, Adams JM: The c-myc oncogene perturbs B lymphocyte development in Eµ-myc transgenic mice. Cell 47: 11–18, 1986

  53. 53.

    Harris AW, Pinkert CA, Crawford M, Langdon WY, Brinster RL, Adams JM: The Eµ-myc transgenic mouse: a model for high incidence spontaneous lymphoma and leukemia of early B cells. J Exp Med 167: 353–371, 1988

  54. 54.

    Schmidt EV, Pattengale PJ, Weir L, Leder P: Transgenic mice bearing the human c-myc gene activated by an immunoglobulin enhancer: a pre B cell lymphoma model. Proc Natl Acad Sci 85: 6047–6051, 1988

  55. 55.

    Land H, Parada LF, Weinberg RA: Tumorigeneic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature 304: 596–601, 1983

  56. 56.

    Sinn E, Muller W, Pattengale P, Tepler I, Wallace R, Leder P: Coexpression of MMTV/v-H-ras and MMTV/c-myc genes in transgenic mice: synergistic action of oncogenesin vivo. Cell 49: 465–475, 1987

  57. 57.

    Verbeek S, van Lohuizen M, van der Valk M, Domen J, Kraal G, Berns A: Mice bearing the Em-myc and Em-pim-1 transgenes develop pre-B cell leukemia prenatally. Mol Cell Biol 11: 1176–1179, 1991

  58. 58.

    Sandgren EP, Luetteke NC, Qui TH, Palmiter RD, Brinster RL, Lee DC: Transforming growth factor alpha dramatically enhances oncogene-induced carcinogenesis in transgenic mouse pancreas and liver. Mol Cell Biol 13: 320–330, 1993

  59. 59.

    Murakami H, Sanderson ND, Nagy P, Marino PA, Merlino G, Thorgeirsson SS: Transgenic mouse model for synergistic effects of nuclear oncogenes and growth factors in tumorigenesis: interaction of c-myc and transforming growth factor alpha in hepatic oncogenesis. Cancer Res 53: 1719–1723, 1993

  60. 60.

    Bisonnette RP, Echeverri F, Mahboubi A, Green DR: Apoptotic cell death induced by c-myc is inhibited bybcl2. Nature 359: 553–554, 1992

  61. 61.

    Fanidi A, Harrington EA, Evan GI: Cooperative interaction between c-myc andbcl2 protooncogenes. Nature 359: 554–556, 1992

  62. 62.

    Stanton BR, Perkins AS, Tessarollo L, Sassoon DA, Parada LF: Loss of N-myc function results in embryonic lethality and failure of the epithelial component of the embryo to develop. Genes Dev 6: 2235–2247, 1993

  63. 63.

    Charron J, Malynn BA, Fisher P, Stewart V, Jeanotte L, Goff SP, Robertson EJ, Alt FW: Embryonic lethality in mice homozygous for a targeted disruption of the N-myc gene. Genes Dev 6: 2248–2257, 1992

  64. 64.

    Davis AC, Wims M, Spotts GD, Hann SR, Bradley A: A null c-myc mutation causes lethality before 10.5 days of gestation in homozygotes and reduced fertility in heterozygous female mice. Genes Dev 7: 671–682, 1993

  65. 65.

    Dressler GR, Wilkinson JE, Rothenspieler UW, Patterson LT, Williams-Simons L, Westphal H: Deregulation of Pax-2 gene expression in transgenic mice generates severe kidney abnormalities. Nature 362: 65–67, 1993

  66. 66.

    Shalaby F, Schuh AC, Breitman ML: Two distinct target cells for v-jun mediated wound tumorigenesis. Oncogene 9: 2579–2588, 1994

  67. 67.

    Cleary ML: Oncogenic conversion of transcription factors by chromosomal translocations. Cell 66: 619–622, 1991

  68. 68.

    Dedera DA, Waller EK, LeBrun DP, Sen-Majumdar A, Stevens ME, Barsh GS, Cleary ML: Chimeric homeobox gene E2A-PBX1 induces proliferation, apoptosis and malignant lymphomas in transgenic mice. Cell 74: 833–843, 1993

  69. 69.

    Lane DP: p53, guardian of the genome. Nature 358: 15–16, 1992

  70. 70.

    Lavigueur A, Maltby V, Mock D, Rossant J, Pawson T, Bernstein A: High incidence of lung, bone and lymphoid tumors in transgenic mice overexpressing mutant alleles of the p53 oncogene. Mol Cell Biol 9: 3982–3991, 1989

  71. 71.

    Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery CA, Butel JS, Bradley A: Mice deficient in p53 are developmentally normal but susceptible to spontaneous tumors. Nature 356: 215–221, 1992

  72. 72.

    Kemp CJ, Donehower LA, Bradley A, Balmain A: Reduction of p53 gene dosage does not increase initiation or promotion but enhances malignant progression of chemically induced skin tumors. Cell 74: 813–822, 1993

  73. 73.

    Symonds H, Krall L, Remington L, Saenz-Robles M, Lowe S, Jacks T, van Dyke T: p53 dependent apoptosis suppresses tumor growth and progressionin vivo. Cell 78: 703–711, 1994

  74. 74.

    Lowe SW, Schmitt EA, Smith SW, Osborne BA, Jacks T: p53 is required for radiation induced apoptosis in mouse thymocytes. Nature 362: 847–849, 1993

  75. 75.

    Clarke AR, Purdie CA, Harrison DJ, Morris RG, Bird CC, Hooper ML, Wyllie AH: Thymocyte apoptosis induced by p53 dependent and independent pathways. Nature 362: 849–852, 1993

  76. 76.

    Lee EYHP, Chang CY, Hu N, Wang YCJ, Lai CC, Herrup K, Lee WH, Bradley A: Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature 359: 288–294, 1992

  77. 77.

    Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA, Weinberg RA: Effects of an Rb mutation in the mouse. Nature 359: 295–300, 1992

  78. 78.

    Clarke AR, Maandag ER, van Roon M, van der Lugt NMT, van der Valk M, Hooper ML, Berns A, te Riele H: Requirement for a functional Rb-1 gene in murine development. Nature 359: 328–330, 1992

  79. 79.

    Morgenbesser SD, Williams BO, Jacks T, DePinho RA: p53 dependent apoptosis produced by Rb deficiency in the developing mouse lens. Nature 371: 72–75, 1994

  80. 80.

    Wang TC, Cardiff RD, Zukerberg L, Lees E, Arnold A, Schmidt EV: Mammary hyperplasia and carcinoma in MMTV/cyclin D1 transgenic mice. Nature 369: 669–671, 1994

  81. 81.

    Lovec H, Grzeschiczek A, Kowalski MB, Moroy T: Cyclin D1bcl-1 cooperates withmyc genes in the generation of lymphoma in transgenic mice. EMBO J 13: 3487–3495, 1994

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Viney, J.L. Transgenic and gene knockout mice in cancer research. Cancer Metast Rev 14, 77–90 (1995).

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Key words

  • cancer
  • tumorigenesis
  • transgenic
  • knockout
  • mice