ErbB2 Transgenic Mice: A Tool for Investigation of the Immune Prevention and Treatment of Mammary Carcinomas

Elena Quaglino1, Cristina Mastini1, Guido Forni1, Federica Cavallo1

1 Molecular Biotechnology Center, Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
Publication Name:  Current Protocols in Immunology
Unit Number:  Unit 20.9
DOI:  10.1002/0471142735.im2009s82
Online Posting Date:  August, 2008
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The epidermal growth factor receptor belongs to a superfamily of receptor tyrosine kinases (RTK) that includes ErbB2. ErbB2 is involved in normal physiological processes, such as embryogenesis, cell proliferation, differentiation, adhesion motility, and apoptosis, while its malfunction or overexpression is responsible for development defects, diabetes, and cancer. The human ortholog of ErbB2 is referred as Her‐2 (human ErbB2) while the rat ortholog is referred as neu (rat ErbB2). As ErbB2 is directly involved in carcinogenesis, mice transgenic for the rat neu oncogene allow straightforward assessment of the ability of drugs and vaccines to inhibit the progression of neu‐driven cancer. Information from this model may provide indications on the efficacy of similar treatments in patients. This commentary provides key information regarding the use of these transgenic mouse models for evaluation of the efficacy of anti‐tumor strategies. Curr. Protoc. Immunol. 82:20.9.1‐20.9.10. © 2008 by John Wiley & Sons, Inc.

Keywords: mammary carcinogenesis; genetically engineered mice; BALB‐neuT‐KO mice; neu transgenic mice; Her‐2 transgenic mice

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Table of Contents

  • Transplantable Versus Transgenic Mouse Cancer Models
  • The ErbB2 Oncogene
  • Mice Transgenic for neu Oncogene
  • BALB‐neuT Mice
  • Prevention Versus Treatment of neu‐Induced Lesions
  • Balb‐neuT Mice Knocked Out (KO) for Immunologically Related Genes
  • Mice Transgenic for the Her‐2 Oncogene
  • Conclusion
  • Acknowledgements
  • Literature Cited
  • Figures
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Literature Cited

Literature Cited
   Ambrosino, E., Spadaro, M., Iezzi, M., Curcio, C., Forni, G., Musiani, P., Wei, W.Z., and Cavallo, F. 2006. Immunosurveillance of Erbb2 carcinogenesis in transgenic mice is concealed by a dominant regulatory T‐cell self‐tolerance. Cancer Res. 66:7734‐7740.
   Andrechek, E.R., Hardy, W.R., Siegel, P.M., Rudnicki, M.A., Cardiff, R.D., and Muller, W.J. 2000. Amplification of the neu/erbB‐2 oncogene in a mouse model of mammary tumorigenesis. Proc. Natl. Acad. Sci. U.S.A. 97:3444‐3449.
   Andrechek, E.R., Laing, M.A., Girgis‐Gabardo, A.A., Siegel, P.M., Cardiff, R.D., and Muller, W.J. 2003. Gene expression profiling of neu‐induced mammary tumors from transgenic mice reveals genetic and morphological similarities to ErbB2‐expressing human breast cancers. Cancer Res. 63:4920‐4926.
   Astolfi, A., Landuzzi, L., Nicoletti, G., De Giovanni, C., Croci, S., Paladini, A., Ferrini, S., Iezzi, M., Musiani, P., Cavallo, F., Forni, G., Nanni, P., and Lollini, P.L. 2005. Gene expression analysis of immune‐mediated arrest of tumorigenesis in a transgenic mouse model of HER‐2/neu‐positive basal‐like mammary carcinoma. Am. J. Pathol. 166:1205‐1216.
   Bargmann, C.I., Hung, M.C., and Weinberg, R.A. 1986. Multiple independent activations of the neu oncogene by a point mutation altering the transmembrane domain of p185. Cell 45:649‐657.
   Boggio, K., Nicoletti, G., Di Carlo, E., Cavallo, F., Landuzzi, L., Melani, C., Giovarelli, M., Rossi, I., Nanni, P., De Giovanni, C., Bouchard, P., Wolf, S., Modesti, A., Musiani, P., Lollini, P.L., Colombo, M.P., and Forni, G. 1998. Interleukin 12–mediated prevention of spontaneous mammary adenocarcinomas in two lines of Her‐2/neu transgenic mice. J. Exp. Med. 188:589‐596.
   Calogero, R.A., Corsero, F., Forni, G., and Cavallo, F. 2007. Inflammation and breast cancer: Inflammatory component of mammary carcinogenesis in ErbB2 transgenic mice. Breast Cancer Res. 9:211.
   Cavallo, F., Curcio, C., and Forni, G. 2005. Immunotherapy and immunoprevention of cancer: Where do we stand? Expert Opin. Biol. Ther. 5:717‐726.
   Cavallo, F., Offringa, R., Van Der Burg, S.H., Forni, G., and Melief, C.J. 2006. Vaccination for treatment and prevention of cancer in animal models. Adv. Immunol. 90:175‐213.
   Cavallo, F., Calogero, R.A., and Forni, G. 2007. Are oncoantigens suitable targets for anti‐tumour therapy? Nat. Rev. Cancer 7:707‐713.
   Chan, R., Muller, W.J., and Siegel, P.M. 1999. Oncogenic activating mutations in the neu/erbB‐2 oncogene are involved in the induction of mammary tumors. Ann. N.Y. Acad. Sci. 889:45‐51.
   Chin, K., DeVries, S., Fridlyand, J., Spellman, P.T., Roydasgupta, R., Kuo, W.L., Lapuk, A., Neve, R.M., Qian, Z., Ryder, T., Chen, F., Feiler, H., Tokuyasu, T., Kingsley, C., Dairkee, S., Meng, Z., Chew, K., Pinkel, D., Jain, A., Ljung, B.M., Esserman, L., Albertson, D.G., Waldman, F.M. and Gray, J.W. 2006. Genomic and transcriptional aberration linked to breast cancer pathophysiologies. Cancer Cell. 10:529‐541.
   Cifaldi, L., Quaglino, E., Di Carlo, E., Musiani, P., Spadaro, M., Lollini, P.L., Wolf, S., Boggio, K., Forni, G., and Cavallo, F. 2001. A light, nontoxic interleukin 12 protocol inhibits HER‐2/neu mammary carcinogenesis in BALB/c transgenic mice with established hyperplasia. Cancer Res. 61:2809‐2812.
   Di Carlo, E., Diodoro, M.G., Boggio, K., Modesti, A., Modesti, M., Nanni, P., Forni, G., and Musiani, P. 1999. Analysis of mammary carcinoma onset and progression in HER‐2/neu oncogene transgenic mice reveals a lobular origin. Lab. Invest. 79:1261‐1269.
   Finkle, D., Quan, Z.R., Asghari, V., Kloss, J., Ghaboosi, N., Mai, E., Wong, W.L., Hollingshead, P., Schwall, R., Koeppen, H., and Erickson, S. 2004. HER2‐targeted therapy reduces incidence and progression of midlife mammary tumors in female murine mammary tumor virus huHER2‐transgenic mice. Clin. Cancer Res. 10:2499‐2511.
   Forni, G., Curcio, C., Spadaio, M., Iliffe, J., Quaglino, E., Di Carlo, E., Musiani, P., and Lollini, P.L. 2003. Immunization in tumor prevention. Int. Immunopharmacol. 3:1151‐1158.
   Förster, R., Schubel, A., Breitfeld, D., Kremmer, E., Renner‐Müller, I., Wolf, E., and Lipp, M. 1999. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell. 99:23‐33.
   Garrett, T.P., McKern, N.M., Lou, M., Elleman, T.C., Adams, T.E., Lovrecz, G.O., Kofler, M., Jorissen, R.N., Nice, E.C., Burgess, A.W., and Ward, C.W. 2003. The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors. Mol. Cell 11:495‐505.
   Green, J.E. and Hudson, T. 2005. The promise of genetically engineered mice for cancer prevention studies. Nat. Rev. Cancer 5:184‐198.
   Guy, C.T., Webster, M.A., Schaller, M., Parsons, T.J., Cardiff, R.D., and Muller, W.J. 1992a. Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc. Natl. Acad. Sci. U.S.A. 89:10578‐10582.
   Guy, C.T., Cardiff, R.D., and Muller, W.J. 1992b. Induction of mammary tumors by expression of polyomavirus middle T oncogene: A transgenic mouse model for metastatic disease. Mol. Cell Biol. 12:954‐961.
   Hayakawa, Y., Rovero, S., Forni, G., and Smyth, M.J. 2003. Alpha‐galactosylceramide (KRN7000) suppression of chemical‐ and oncogene‐dependent carcinogenesis. Proc. Natl. Acad. Sci. U.S.A. 100:9464‐9469.
   Hirsch, E., Katanaev, V.L., Garlanda, C., Azzolino, O., Pirola, L., Silengo, L., Sozzani, S., Mantovani, A., Altruda, F., and Wymann, M.P. 2000. Central role for G protein‐coupled phosphoinositide 3‐kinase gamma in inflammation. Science 287:1049‐1053.
   Hüsemann, Y., Geigl, J.B., Schubert, F., Musiani, P., Meyer, M., Burghart, E., Forni, G., Eils, R., Fehm, T., Riethmüller, G., and Klein, C.A. 2008. Systemic spread is an early step in breast cancer. Cancer Cell 13:58‐68.
   Kamb, A. 2005. What's wrong with our cancer models? Nat. Rev. Drug Discov. 4:161‐165.
   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.
   Kwong, K.Y. and Hung, M.C. 1998. A novel splice variant of HER2 with increased transformation activity. Mol. Carcinog. 23:62‐68.
   Lin, E.Y., Jones, J.G., Li, P., Zhu, L., Whitney, K.D., Muller, W.J., and Pollard, J.W. 2003. Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am. J. Pathol. 163:2113‐2126.
   Lollini, P.L., Nicoletti, G., Landuzzi, L., De Giovanni, C., and Nanni, P. 2005. New target antigens for cancer immunoprevention. Curr. Cancer Drug Targets 5:221‐228.
   Lucchini, F., Sacco, M.G., Hu, N., Villa, A., Brown, J., Cesano, L., Mangiarini, L., Rindi, G., Kindl, S., Sessa, F., Vezzoni, P., and Clerici, L. 1992. Early and multifocal tumors in breast, salivary, harderian and epididymal tissues developed in MMTY‐Neu transgenic mice. Cancer Lett. 64:203‐209.
   Marty, M., Cognetti, F., Maraninchi, D., Snyder, R., Mauriac, L., Tubiana‐Hulin, M., Chan, S., Grimes, D., Antón, A., Lluch, A., Kennedy, J., O'Byrne, K., Conte, P., Green, M., Ward, C., Mayne, K., and Extra, J.M. 2005. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2‐positive metastatic breast cancer administered as first‐line treatment: The M77001 study group. J. Clin. Oncol. 23:4265‐4274.
   Melani, C., Chiodoni, C., Forni, G., and Colombo, M.P. 2003. Myeloid cell expansion elicited by the progression of spontaneous mammary carcinomas in c‐erbB‐2 transgenic BALB/c mice suppresses immune reactivity. Blood 102:2138‐2145.
   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.
   Nanni, P., Nicoletti, G., De Giovanni, C., Landuzzi, L., Di Carlo, E., Cavallo, F., Pupa, S.M., Rossi, I., Colombo, M.P., Ricci, C., Astolfi, A., Musiani, P., Forni, G., and Lollini, P.L. 2001. Combined allogeneic tumor cell vaccination and systemic IL12 prevents mammary carcinogenesis in HER‐2/neu transgenic mice. J. Exp. Med. 194:1195‐1205.
   Ostrand‐Rosenberg, S. 2004. Animal models of tumor immunity, immunotherapy and cancer vaccines. Curr. Opin. Immunol. 16:143‐150.
   Piechocki, M.P., Ho, Y.S., Pilon, S., and Wei, W.Z. 2003. Human ErbB‐2 (Her‐2) transgenic mice: A model system for testing Her‐2 based vaccines. J. Immunol. 171:5787‐5794.
   Quaglino, E., Rolla, S., Iezzi, M., Spadaio, M., Musiani, P., De Giovanni, C., Lollini, P.L., Lanzardo, S., Forni, G., Sanges, R., Crispi, S., De Luca, P., Calogero, R., and Cavallo, F. 2004a. Concordant morphologic and gene expression data show that a vaccine halt HER‐2/neu preneoplastic lesions. J. Clin. Invest. 113:709‐717.
   Quaglino, E., Iezzi, M., Mastini, C., Amici, A., Pericle, F., Di Carlo, E., Pupa, S.M., De Giovanni, C., Spadaro, M., Curcio, C., Lollini, P.L., Musiani, P., Forni, G., and Cavallo, F. 2004b. Electroporated DNA vaccine clears away multifocal mammary carcinomas in her‐2/neu transgenic mice. Cancer Res. 64:2858‐2864.
   Rolla, S., Nicoló, C., Malinarich, S., Orsini, M., Forni, G., Cavallo, F., and Ria, F. 2006. Distinct and non‐overlapping T cell receptor repertoires expanded by DNA vaccination in wild‐type and HER‐2 transgenic BALB/c mice. J. Immunol. 177:7626‐7633.
   Shih, C., Padhy, L.C., Murray, M., and Weinberg, R.A. 1981. Transforming genes of carcinomas and neuroblastomas introduced into mouse fibroblasts. Nature 290:261‐264.
   Siegel, P.M., Ryan, E.D., Cardiff, R.D., and Muller, W.J. 1999. Elevated expression of activated forms of Neu/ErbB‐2 and ErbB‐3 are involved in the induction of mammary tumors in transgenic mice: Implications for human breast cancer. EMBO J. 18:2149‐2164.
   Spadaro, M., Lanzardo, S., Curcio, C., Forni, G., and Cavallo, F. 2004. Immunological inhibition of carcinogenesis. Cancer Immunol. Immunother. 53:204‐216.
   Stöcklin, E., Botteri, F., and Groner, B. 1993. An activated allele of the c‐erbB‐2 oncogene impairs kidney and lung function and causes early death of transgenic mice. J. Cell Biol. 122:199‐208.
   Street, S.E., Zerafa, N., Iezzi, M., Westwood, JA., Stagg, J., Musiani, P., and Smyth, M.J. 2007. Host perforin reduces tumor number but does not increase survival in oncogene‐driven mammary adenocarcinoma. Cancer Res. 67:5454‐5460.
   Takai, T., Li, M., Sylvestre, D., Clynes, R., and Ravetch, J.V. 1994. FcR gamma chain deletion results in pleiotrophic effector cell defects. Cell 76:519‐529.
   Trapani, J.A. and Smyth, M.J. 2002. Functional significance of the perforin/granzyme cell death pathway. Nat. Rev. Immunol. 2:735‐747.
   Ursini‐Siegel, J., Schade, B., Cardiff, R.D., and Muller, W.J. 2007. Insights from transgenic mouse models of ERBB2‐induced breast cancer. Nat. Rev. Cancer. 7:389‐397.
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