The RCAS/TVA Somatic Gene Transfer Method in Modeling Human Cancer

  • Yi LiEmail author
  • Andrea Ferris
  • Brian C. Lewis
  • Sandra Orsulic
  • Bart O. Williams
  • Eric C. Holland
  • Stephen H. Hughes


Most human solid cancers arise from one or a few mutated cells in an otherwise normally developed tissue. In order to understand the genetic and cellular basis of these tumors, it is necessary to have models that can closely recapitulate such an evolutionary process. Many mouse models have been reported using genetic engineering, but in most of them the causal genetic alteration is introduced into the genome of all or the majority of cells in a tissue to be studied, and causes developmental abnormality. The RCAS/TVA gene transfer method offers an attractive alternative, with which oncogenic mutations can be engineered into a small number of cells, with cell type selectivity, and after the organ development has completed.


Murine Leukemia Virus Exogenous Gene Rous Sarcoma Virus Internal Promoter Nondividing Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank Drs. Harold Varmus, Sheri Holmen, Vidya Sinha, and Gary Chamness for critical comments on this manuscript. This research was supported in part by National Institutes of Health R01 CA113869 and CA124820 (to YL) and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (to SHH).


  1. Adkins HB, Brojatsch J, Young JA (2000) Identification and characterization of a shared TNFR-related receptor for subgroup B, D, and E avian leukosis viruses reveal cysteine residues required specifically for subgroup E viral entry. J Virol 74:3572–3578PubMedCrossRefGoogle Scholar
  2. Barr SD, Leipzig J, Shinn P, Ecker JR, Bushman FD (2005) Integration targeting by avian sarcoma-leukosis virus and human immunodeficiency virus in the chicken genome. J Virol 79:12035–12044PubMedCrossRefGoogle Scholar
  3. Barsov EV, Hughes SH (1996) Gene transfer into mammalian cells by a Rous sarcoma virus-based retroviral vector with the host range of the amphotropic murine leukemia virus. J Virol 70:3922–3929PubMedGoogle Scholar
  4. Barsov EV, Payne WS, and Hughes SH (2001) Adaptation of chimeric retroviruses in vitro and in vivo: isolation of avian retroviral vectors with extended host range. J Virol 75:4973–4983PubMedGoogle Scholar
  5. Bates P, Young JA, Varmus HE (1993) A receptor for subgroup A Rous sarcoma virus is related to the low density lipoprotein receptor. Cell 74:1043–1051PubMedCrossRefGoogle Scholar
  6. Boerkoel CF, Federspiel MJ, Salter DW, Payne W, Crittenden LB, Kung HJ, Hughes SH (1993) A new defective retroviral vector system based on the Bryan strain of Rous sarcoma virus. Virology 195:669–679PubMedCrossRefGoogle Scholar
  7. Boulanger CA, Wagner KU, Smith GH (2005) Parity-induced mouse mammary epithelial cells are pluripotent, self-renewing and sensitive to TGF-beta1 expression. Oncogene 24(4):552–560PubMedCrossRefGoogle Scholar
  8. Brojatsch J, Naughton J, Rolls MM, Zingler K, Young JA (1996) CAR1, a TNFR-related protein, is a cellular receptor for cytopathic avian leukosis-sarcoma viruses and mediates apoptosis. Cell 87:845–855PubMedCrossRefGoogle Scholar
  9. Buendia MA (2000) Genetics of hepatocellular carcinoma. Semin Cancer Biol 10:185–200PubMedCrossRefGoogle Scholar
  10. Bu W, Chen J, Morrison GD, Huang S, Creighton CJ, Huang J, Chamness GC, Hilsenbeck SG, Roop DR, Leavitt AD (2011) Keratin 6a marks mammary bipotential progenitor cells that can give rise to a unique tumor model resembling human normal-like breast cancer. Oncogene Epub May 2, 2011PubMedCrossRefGoogle Scholar
  11. Chai N, Bates P (2006) Na+/H+ exchanger type 1 is a receptor for pathogenic subgroup J avian leukosis virus. Proc Natl Acad Sci USA 103:5531–5536PubMedCrossRefGoogle Scholar
  12. Chang KW, Barsov EV, Ferris AL, Hughes SH (2005) Mutations of a residue within the polyproline-rich region of Env alter the replication rate and level of cytopathic effects in chimeric avian retroviral vectors. J Virol 79:10258–10267PubMedCrossRefGoogle Scholar
  13. Chen YW, Klimstra DS, Mongeau ME, Tatem JL, Boyartchuk V, Lewis BC (2007) Loss of p53 and Ink4a/Arf cooperate in a cell autonomous fashion to induce metastasis of hepatocellular carcinoma cells. Cancer Res 67:7589–7596PubMedCrossRefGoogle Scholar
  14. Chen YW, Paliwal S, Draheim K, Grossman SR, Lewis BC (2008) p19Arf inhibits the invasion of hepatocellular carcinoma cells by binding to C-terminal binding protein. Cancer Res 68:476–482PubMedCrossRefGoogle Scholar
  15. Chiang MK, Melton DA (2003) Single-cell transcript analysis of pancreas development. Dev Cell 4:383–393PubMedCrossRefGoogle Scholar
  16. Clarke MF, Fuller M (2006) Stem cells and cancer: two faces of eve. Cell 124:1111–1115PubMedCrossRefGoogle Scholar
  17. Dai C, Celestino JC, Okada Y, Louis DN, Fuller GN, Holland EC (2001) PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo. Genes Dev 15:1913–1925PubMedCrossRefGoogle Scholar
  18. Dai C, Lyustikman Y, Shih A, Hu X, Fuller GN, Rosenblum M, Holland EC (2005) The characteristics of astrocytomas and oligodendrogliomas are caused by two distinct and interchangeable signaling formats. Neoplasia 7:397–406PubMedCrossRefGoogle Scholar
  19. Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A (1999) Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97:703–716PubMedCrossRefGoogle Scholar
  20. Du YC, Lewis BC, Hanahan D, Varmus H (2007) Assessing tumor progression factors by somatic gene transfer into a mouse model: Bcl-xL promotes islet tumor cell invasion. PLoS Biol 5:2255–2269CrossRefGoogle Scholar
  21. Du Z, Podsypanina K, Huang H, McGrath A, Toneff MJ, Bogoslovskaia E, Zhang X, Moraes RC, Fluck MM, Allred DC et al (2006) Introduction of oncogenes into mammary glands in vivo with an avian retroviral vector initiates and promotes carcinogenesis in mouse models. Proc Natl Acad Sci USA 103:17396–17401PubMedCrossRefGoogle Scholar
  22. Dunn KJ, Brady M, Ochsenbauer-Jambor C, Snyder S, Incao A, Pavan WJ (2005) WNT1 and WNT3a promote expansion of melanocytes through distinct modes of action. Pigment Cell Res 18:167–180PubMedCrossRefGoogle Scholar
  23. Dunn KJ, Incao A, Watkins-Chow D, Li Y, Pavan WJ (2001) In utero complementation of a neural crest-derived melanocyte defect using cell directed gene transfer. Genesis 30:70–76PubMedCrossRefGoogle Scholar
  24. Dunn KJ, Williams BO, Li Y, Pavan WJ (2000) Neural crest-directed gene transfer demonstrates Wnt1 role in melanocyte expansion and differentiation during mouse development. Proc Natl Acad Sci USA 97:10050–10055PubMedCrossRefGoogle Scholar
  25. Elleder D, Stepanets V, Melder DC, Senigl F, Geryk J, Pajer P, Plachy J, Hejnar J, Svoboda J, Federspiel MJ (2005) The receptor for the subgroup C avian sarcoma and leukosis viruses, Tvc, is related to mammalian butyrophilins, members of the immunoglobulin superfamily. J Virol 79:10408–10419PubMedCrossRefGoogle Scholar
  26. Federspiel MJ, Bates P, Young JA, Varmus HE, Hughes SH (1994) A system for tissue-specific gene targeting: transgenic mice susceptible to subgroup A avian leukosis virus-based retroviral vectors. Proc Natl Acad Sci USA 91:11241–11245PubMedCrossRefGoogle Scholar
  27. Ferletta M, Uhrbom L, Olofsson T, Ponten F, Westermark B (2007) Sox10 has a broad expression pattern in gliomas and enhances platelet-derived growth factor-B-induced gliomagenesis. Mol Cancer Res 5:891–897PubMedCrossRefGoogle Scholar
  28. Fu SL, Huang YJ, Liang FP, Huang YF, Chuang CF, Wang SW, Yao JW (2005) Malignant transformation of an epithelial cell by v-Src via tv-a-mediated retroviral infection: a new cell model for studying carcinogenesis. Biochem Biophys Res Commun 338:830–838PubMedCrossRefGoogle Scholar
  29. Fults D, Pedone C, Dai C, Holland EC (2002) MYC expression promotes the proliferation of neural progenitor cells in culture and in vivo. Neoplasia 4:32–39PubMedCrossRefGoogle Scholar
  30. Gaur M, Murphy GJ, deSauvage FJ, Leavitt AD (2001) Characterization of Mpl mutants using primary megakaryocyte-lineage cells from mpl(−/−) mice: a new system for Mpl structure-function studies. Blood 97:1653–1661PubMedCrossRefGoogle Scholar
  31. Hambardzumyan D, Becher OJ, Rosenblum MK, Pandolfi PP, Manova-Todorova K, Holland EC (2008) PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo. Genes Dev 22:436–448PubMedCrossRefGoogle Scholar
  32. Hanafusa H, Hanafusa T, Rubin H (1963) The defectiveness of Rous sarcoma virus. Proc Natl Acad Sci USA 49:572–580PubMedCrossRefGoogle Scholar
  33. Hatziioannou T, Goff SP (2001) Infection of nondividing cells by Rous sarcoma virus. J Virol 75:9526–9531PubMedCrossRefGoogle Scholar
  34. Hezel AF, Kimmelman AC, Stanger BZ, Bardeesy N, Depinho RA (2006) Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev 20:1218–1249PubMedCrossRefGoogle Scholar
  35. Himly M, Foster DN, Bottoli I, Iacovoni JS, Vogt PK (1998) The DF-1 chicken fibroblast cell line: transformation induced by diverse oncogenes and cell death resulting from infection by avian leukosis viruses. Virology 248:295–304PubMedCrossRefGoogle Scholar
  36. Holland EC, Celestino J, Dai C, Schaefer L, Sawaya RE, Fuller GN (2000a) Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet 25:55–57PubMedCrossRefGoogle Scholar
  37. Holland EC, Hively WP, DePinho RA, Varmus HE (1998) A constitutively active epidermal growth factor receptor cooperates with disruption of G1 cell-cycle arrest pathways to induce glioma-like lesions in mice [In Process Citation]. Genes Dev 12:3675–3685PubMedCrossRefGoogle Scholar
  38. Holland EC, Li Y, Celestino J, Dai C, Schaefer L, Sawaya RA, Fuller GN (2000b) Astrocytes give rise to oligodendrogliomas and astrocytomas after gene transfer of polyoma virus middle T antigen in vivo. Am J Pathol 157:1031–1037PubMedCrossRefGoogle Scholar
  39. Holland EC, Varmus HE (1998) Basic fibroblast growth factor induces cell migration and proliferation after glia-specific gene transfer in mice. Proc Natl Acad Sci USA 95:1218–1223PubMedCrossRefGoogle Scholar
  40. Holmen SL, Williams BO (2005) Essential role for Ras signaling in glioblastoma maintenance. Cancer Res 65:8250–8255PubMedCrossRefGoogle Scholar
  41. Hou L, Loftus SK, Incao A, Chen A, Pavan WJ (2004) Complementation of melanocyte development in SOX10 mutant neural crest using lineage-directed gene transfer. Dev Dyn 229:54–62PubMedCrossRefGoogle Scholar
  42. Hu J, Ferris A, Larochelle A, Krouse AE, Metzger ME, Donahue RE, Hughes SH, Dunbar CE (2007) Transduction of rhesus macaque hematopoietic stem and progenitor cells with avian sarcoma and leukosis virus vectors. Hum Gene Ther 18:691–700PubMedCrossRefGoogle Scholar
  43. Hu J, Renaud G, Ferris A, Hendrie PC, Donahue RE, Hughes SH, Wolfsberg TG, Russell DW, Dunbar CE (2008) Reduced genotoxicity of avian sarcoma leukosis virus vectors in rhesus long-term repopulating cells compared to standard murine retrovirus vectors. Mol Ther 16(9):1617–1623PubMedCrossRefGoogle Scholar
  44. Hu X, Pandolfi PP, Li Y, Koutcher JA, Rosenblum M, Holland EC (2005) mTOR promotes survival and astrocytic characteristics induced by Pten/AKT signaling in glioblastoma. Neoplasia 7:356–368PubMedCrossRefGoogle Scholar
  45. Hughes SH (2004) The RCAS vector system. Folia Biol (Praha) 50:107–119Google Scholar
  46. Hughes SH, Greenhouse JJ, Petropoulos CJ, Sutrave P (1987) Adaptor plasmids simplify the insertion of foreign DNA into helper-independent retroviral vectors. J Virol 61:3004–3012PubMedGoogle Scholar
  47. Katz RA, Greger JG, Darby K, Boimel P, Rall GF, Skalka AM (2002) Transduction of interphase cells by avian sarcoma virus. J Virol 76:5422–5434PubMedCrossRefGoogle Scholar
  48. Katz RA, Jack-Scott E, Narezkina A, Palagin I, Boimel P, Kulkosky J, Nicolas E, Greger JG, Skalka AM (2007) High-frequency epigenetic repression and silencing of retroviruses can be antagonized by histone deacetylase inhibitors and transcriptional activators, but uniform reactivation in cell clones is restricted by additional mechanisms. J Virol 81:2592–2604PubMedCrossRefGoogle Scholar
  49. Kim H, You S, Kim IJ, Farris J, Foster LK, Foster DN (2001) Increased mitochondrial-encoded gene transcription in immortal DF-1 cells. Exp Cell Res 265:339–347PubMedCrossRefGoogle Scholar
  50. Koo BC, Kwon MS, Choi BR, Lee HT, Choi HJ, Kim JH, Kim NH, Jeon I, Chang W, Kim T (2004) Retrovirus-mediated gene transfer and expression of EGFP in chicken. Mol Reprod Dev 68:429–434PubMedCrossRefGoogle Scholar
  51. Lassman AB, Dai C, Fuller GN, Vickers AJ, Holland EC (2004) Overexpression of c-MYC promotes an undifferentiated phenotype in cultured astrocytes and allows elevated Ras and Akt signaling to induce gliomas from GFAP-expressing cells in mice. Neuron Glia Biol 1:157–163PubMedCrossRefGoogle Scholar
  52. Lee JW, Soung YH, Kim SY, Lee HW, Park WS, Nam SW, Kim SH, Lee JY, Yoo NJ, Lee SH (2005) PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas. Oncogene 24:1477–1480PubMedCrossRefGoogle Scholar
  53. Lendahl U, Zimmerman LB, McKay RD (1990) CNS stem cells express a new class of intermediate filament protein. Cell 60:585–595PubMedCrossRefGoogle Scholar
  54. Lewis BC, Chinnasamy N, Morgan RA, Varmus HE (2001) Development of an avian leukosis-sarcoma virus subgroup A pseudotyped lentiviral vector. J Virol 75:9339–9344PubMedCrossRefGoogle Scholar
  55. Lewis BC, Klimstra DS, Socci ND, Xu S, Koutcher JA, Varmus HE (2005) The absence of p53 promotes metastasis in a novel somatic mouse model for hepatocellular carcinoma. Mol Cell Biol 25:1228–1237PubMedCrossRefGoogle Scholar
  56. Lewis BC, Klimstra DS, Varmus HE (2003) The c-myc and PyMT oncogenes induce different tumor types in a somatic mouse model for pancreatic cancer. Genes Dev 17:3127–3138PubMedCrossRefGoogle Scholar
  57. Li Z, Tognon CE, Godinho FJ, Yasaitis L, Hock H, Herschkowitz JI, Lannon CL, Cho E, Kim SJ, Bronson RT et al (2007) ETV6-NTRK3 fusion oncogene initiates breast cancer from committed mammary progenitors via activation of AP1 complex. Cancer Cell 12:542–558PubMedCrossRefGoogle Scholar
  58. Liu Y, Yeh N, Zhu XH, Leversha M, Cordon-Cardo C, Ghossein R, Singh B, Holland E, Koff A (2007) Somatic cell type specific gene transfer reveals a tumor-promoting function for p21(Waf1/Cip1). EMBO J 26:4683–4693PubMedCrossRefGoogle Scholar
  59. Loftus SK, Larson DM, Watkins-Chow D, Church DM, Pavan WJ (2001) Generation of RCAS vectors useful for functional genomic analyses. DNA Res 8:221–226PubMedCrossRefGoogle Scholar
  60. Matulka LA, Triplett AA, Wagner KU (2007) Parity-induced mammary epithelial cells are multipotent and express cell surface markers associated with stem cells. Dev Biol 303:29–44PubMedCrossRefGoogle Scholar
  61. Miao J, Wang Z, Provencher H, Muir B, Dahiya S, Carney E, Leong CO, Sgroi DC, and Orsulic S (2007) HOXB13 promotes ovarian cancer progression. Proc Natl Acad Sci USA 104:17093–17098PubMedCrossRefGoogle Scholar
  62. Momota H, Shih AH, Edgar MA, Holland EC (2008) c-Myc and beta-catenin cooperate with loss of p53 to generate multiple members of the primitive neuroectodermal tumor family in mice. Oncogene 27(32):4392–4401PubMedCrossRefGoogle Scholar
  63. Montaner S, Sodhi A, Molinolo A, Bugge TH, Sawai ET, He Y, Li Y, Ray PE, Gutkind JS (2003) Endothelial infection with KSHV genes in vivo reveals that vGPCR initiates Kaposi’s sarcomagenesis and can promote the tumorigenic potential of viral latent genes. Cancer Cell 3:23–36PubMedCrossRefGoogle Scholar
  64. Morton JP, Klimstra DS, Mongeau ME, Lewis BC (2008) Trp53 deletion stimulates the formation of metastatic pancreatic tumors. Am J Pathol 172:1081–1087PubMedCrossRefGoogle Scholar
  65. Morton JP, Mongeau ME, Klimstra DS, Morris JP, Lee YC, Kawaguchi Y, Wright CV, Hebrok M, Lewis BC (2007) Sonic hedgehog acts at multiple stages during pancreatic tumorigenesis. Proc Natl Acad Sci USA 104:5103–5108PubMedCrossRefGoogle Scholar
  66. Mothes W, Boerger AL, Narayan S, Cunningham JM, Young JA (2000) Retroviral entry mediated by receptor priming and low pH triggering of an envelope glycoprotein. Cell 103:679–689PubMedCrossRefGoogle Scholar
  67. Murphy GJ, Gottgens B, Vegiopoulos A, Sanchez MJ, Leavitt AD, Watson SP, Green AR, Frampton J (2003) Manipulation of mouse hematopoietic progenitors by specific retroviral infection. J Biol Chem 278:43556–43563PubMedCrossRefGoogle Scholar
  68. Murphy GJ, Leavitt AD (1999) A model for studying megakaryocyte development and biology. Proc Natl Acad Sci USA 96:3065–3070PubMedCrossRefGoogle Scholar
  69. Nasioulas G, Hughes SH, Felber BK, Whitcomb JM (1995) Production of avian leukosis virus particles in mammalian cells can be mediated by the interaction of the human immunodeficiency virus protein Rev and the Rev-responsive element. Proc Natl Acad Sci USA 92:11940–11944PubMedCrossRefGoogle Scholar
  70. Nguyen D, Beeman N, Lewis MT, Schaack J, Neville MC (2000) Intraductal injection into the mouse mammary gland. In: Ip MM, Asch BB (eds) Methods in mammay gland biology and breast cancer research. Kluwer, New York, pp 259–270CrossRefGoogle Scholar
  71. Nusse R, Varmus HE (1982) Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 31:99–109PubMedCrossRefGoogle Scholar
  72. Orsulic S, Li Y, Soslow RA, Vitale-Cross LA, Gutkind JS, Varmus HE (2002) Induction of ovarian cancer by defined multiple genetic changes in a mouse model system. Cancer Cell 1:53–62PubMedCrossRefGoogle Scholar
  73. Pao W, Klimstra DS, Fisher GH, Varmus HE (2003) Use of avian retroviral vectors to introduce transcriptional regulators into mammalian cells for analyses of tumor maintenance. Proc Natl Acad Sci USA 100:8764–8769PubMedCrossRefGoogle Scholar
  74. Petropoulos CJ, Hughes SH (1991) Replication-competent retrovirus vectors for the transfer and expression of gene cassettes in avian cells. J Virol 65:3728–3737PubMedGoogle Scholar
  75. Pinto VB, Prasad S, Yewdell J, Bennink J, Hughes SH (2000) Restricting expression prolongs expression of foreign genes introduced into animals by retroviruses. J Virol 74:10202–10206PubMedCrossRefGoogle Scholar
  76. Pizzato M, Popova E, Gottlinger HG (2008) Nef can enhance the infectivity of receptor-pseudotyped human immunodeficiency virus type 1 particles. J Virol 82(21):10811–10819PubMedCrossRefGoogle Scholar
  77. Rao G, Pedone CA, Del Valle L, Reiss K, Holland EC, Fults DW (2004) Sonic hedgehog and insulin-like growth factor signaling synergize to induce medulloblastoma formation from nestin-expressing neural progenitors in mice. Oncogene 23:6156–6162PubMedCrossRefGoogle Scholar
  78. Reddy JP, Peddibhotla S, Bu W, Zhao J, Haricharan S, Du YC, Podsypanina K, Rosen JM, Donehower LA, and Li Y (2010) Defining the ATM-mediated barrier to tumorigenesis in somatic mammary cells following ErbB2 activation. Proceedings of the National Academy of Sciences of the United States of America 107:3728–3733PubMedCrossRefGoogle Scholar
  79. Robinson GW, McKnight RA, Smith GH, Hennighausen L (1995) Mammary epithelial cells undergo secretory differentiation in cycling virgins but require pregnancy for the establishment of terminal differentiation. Development 121:2079–2090PubMedGoogle Scholar
  80. Robinson JP, Vanbrocklin MW, Lastwika KJ, McKinney AJ, Brandner S, and Holmen SL (2010) Activated MEK cooperates with Ink4a/Arf loss or Akt activation to induce gliomas in vivo. Oncogene.PubMedGoogle Scholar
  81. Sausville J, Molinolo AA, Cheng X, Frampton J, Takebe N, Gutkind JS, Feldman RA (2008) RCAS/SCL-TVA animal model allows targeted delivery of polyoma middle T oncogene to vascular endothelial progenitors in vivo and results in hemangioma development. Clin Cancer Res 14:3948–3955PubMedCrossRefGoogle Scholar
  82. Schaefer-Klein J, Givol I, Barsov EV, Whitcomb JM, VanBrocklin M, Foster DN, Federspiel MJ, Hughes SH (1998) The EV-O-derived cell line DF-1 supports the efficient replication of avian leukosis-sarcoma viruses and vectors. Virology 248:305–311PubMedCrossRefGoogle Scholar
  83. Seidler B, Schmidt A, Mayr U, Nakhai H, Schmid RM, Schneider G, Saur D (2008) A Cre-loxP-based mouse model for conditional somatic gene expression and knockdown in vivo by using avian retroviral vectors. Proc Natl Acad Sci USA 105:10137–10142PubMedCrossRefGoogle Scholar
  84. Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, Asselin-Labat ML, Wu L, Lindeman GJ, Visvader JE (2006) Generation of a functional mammary gland from a single stem cell. Nature 439:84–88PubMedCrossRefGoogle Scholar
  85. Siwko S, Bu W, Gutierrez C, Lewis BC, Jechlinger M, Schaffhausen B, Li Y (2008) Lentivirus-mediated oncogene introduction into mammary cells in vivo induces tumors. Neoplasia 11:653–662Google Scholar
  86. Sodhi A, Montaner S, Patel V, Gomez-Roman JJ, Li Y, Sausville EA, Sawai ET, Gutkind JS (2004) Akt plays a central role in sarcomagenesis induced by Kaposi’s sarcoma herpesvirus-encoded G protein-coupled receptor. Proc Natl Acad Sci USA 101:4821–4826PubMedCrossRefGoogle Scholar
  87. Stingl J, Eirew P, Ricketson I, Shackleton M, Vaillant F, Choi D, Li HI, Eaves CJ (2006) Purification and unique properties of mammary epithelial stem cells. Nature 439:993–997PubMedGoogle Scholar
  88. Theodorou V, Kimm MA, Boer M, Wessels L, Theelen W, Jonkers J, Hilkens J (2007) MMTV insertional mutagenesis identifies genes, gene families and pathways involved in mammary cancer. Nat Genet 39:759–769PubMedCrossRefGoogle Scholar
  89. Uhrbom L, Dai C, Celestino JC, Rosenblum MK, Fuller GN, Holland EC (2002) Ink4a-Arf loss cooperates with KRas activation in astrocytes and neural progenitors to generate glioblastomas of various morphologies depending on activated Akt. Cancer Res 62:5551–5558PubMedGoogle Scholar
  90. VanBrocklin MW, Robinson JP, Lastwika KJ, Khoury JD, and Holmen SL (2010) Targeted delivery of NRASQ61R and Cre-recombinase to post-natal melanocytes induces melanoma in Ink4a/Arflox/lox mice. Pigment Cell Melanoma Res 23:531–541PubMedCrossRefGoogle Scholar
  91. Vervoort VS, Lu M, Valencia F, Lesperance J, Breier G, Oshima R, Pasquale EB (2008) A novel Flk1-TVA transgenic mouse model for gene delivery to angiogenic vasculature. Transgenic Res 17:403–415PubMedCrossRefGoogle Scholar
  92. Whitwam T, Vanbrocklin MW, Russo ME, Haak PT, Bilgili D, Resau JH, Koo HM, Holmen SL (2007) Differential oncogenic potential of activated RAS isoforms in melanocytes. Oncogene 26:4563–4570PubMedCrossRefGoogle Scholar
  93. Wicha MS, Liu S, Dontu G (2006) Cancer stem cells: an old idea – a paradigm shift. Cancer Res 66:1883–1890PubMedCrossRefGoogle Scholar
  94. Wolf RM, Draghi N, Liang X, Dai C, Uhrbom L, Eklof C, Westermark B, Holland EC, Resh MD (2003) p190RhoGAP can act to inhibit PDGF-induced gliomas in mice: a putative tumor suppressor encoded on human chromosome 19q13.3. Genes Dev 17:476–487PubMedCrossRefGoogle Scholar
  95. Xing D, and Orsulic S (2005a) A genetically defined mouse ovarian carcinoma model for the molecular characterization of pathway-targeted therapy and tumor resistance. Proc Natl Acad Sci USA 102:6936–6941PubMedGoogle Scholar
  96. Xing D, and Orsulic S (2005b) Modeling resistance to pathway-targeted therapy in ovarian cancer. Cell Cycle 4:1004–1006PubMedGoogle Scholar
  97. Xing D, and Orsulic S (2006) A mouse model for the molecular characterization of brca1-associated ovarian carcinoma. Cancer Res 66:8949–8953PubMedGoogle Scholar
  98. Young JA, Bates P, Varmus HE (1993) Isolation of a chicken gene that confers susceptibility to infection by subgroup A avian leukosis and sarcoma viruses. J Virol 67:1811–1816PubMedGoogle Scholar
  99. Zheng XH, Hughes SH (1999) An avian sarcoma/leukosis virus-based gene trap vector for mammalian cells. J Virol 73:6946–6952PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Yi Li
    • 1
    Email author
  • Andrea Ferris
    • 2
  • Brian C. Lewis
    • 3
  • Sandra Orsulic
    • 4
  • Bart O. Williams
    • 5
  • Eric C. Holland
    • 6
  • Stephen H. Hughes
    • 2
  1. 1.Lester and Sue Smith Breast Center and Department of Molecular and Cell BiologyBaylor College of MedicineHoustonUSA
  2. 2.HIV Drug Resistance ProgramNational Cancer Institute-FrederickFrederickUSA
  3. 3.Program in Gene Function and ExpressionUniversity of Massachusetts Medical CenterWorcesterUSA
  4. 4.Women’s Cancer Research InstituteCedars-Sinai Medical CenterLos AngelesUSA
  5. 5.Molecular Medicine and Virology GroupVan Andel Research InstituteGrand RapidsUSA
  6. 6.Program in Cancer Biology and GeneticsMemorial Sloan Kettering Cancer CenterNew YorkUSA

Personalised recommendations