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Signal Transduction in Transgenic Mouse Models of Human Breast Cancer—Implications for Human Breast Cancer

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Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

The advent of genetically engineered mouse models (GEMs) of human breast cancer, have provided important insight into molecular basis or human breast cancer. This review will focus on two of the most extensively studied mouse models for human breast cancer involving mammary gland specific expression of the polyoma middle T (PyV MT) antigen and of the ErbB2. In addition, this review will discuss past and recent advances in understanding relative contribution of the signaling pathways in tumor induction and metastasis by these potent mammary oncogenes.

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Abbreviations

CKI:

cyclin kinase inhibitors

DCIS:

ductal carcinoma in situ

ECM:

extracellular matrix

EGFR:

epidermal growth factor receptor

EMT:

epithelial to mesenchymal transition

ERα:

estrogen receptor α

FAK:

focal adhesion kinase

GEM:

genetically-engineered mouse

IGF-1R:

insulin-like growth factor-1 receptor

IKK:

IκB kinase

IR:

insulin receptor

IRS:

insulin receptor substrates

LOH:

loss of heterozygosity

MMP:

matrix metalloproteinases

MMTV:

mouse mammary tumor virus

PTP1B:

protein tyrosine phosphatase 1B

PyV MT:

polyoma middle T

RCAS:

replication-competent avian leukosis virus long terminal repeat with splice acceptor

TGF-β:

transforming growth factor-β

TβRII:

TGF-β type II receptor

TIMP:

tissue inhibitors of metalloproteinases

uPa:

urokinase-type plasminogen activator

VEGF-R:

vascular endothelial growth factor receptor

WAP:

whey acidic protein

Wip:

wildtype p53-induced phosphatase 1

References

  1. Lester J. Breast cancer in 2007: incidence, risk assessment, and risk reduction strategies. Clin J Oncol Nurs 2007;11 (5):619–22.

    Article  PubMed  Google Scholar 

  2. Cardiff RD, Anver MR, Gusterson BA, Hennighausen L, Jensen RA, Merino MJ, et al. The mammary pathology of genetically engineered mice: the consensus report and recommendations from the Annapolis meeting. Oncogene 2000;19 (8):968–88.

    Article  PubMed  CAS  Google Scholar 

  3. Callahan R, Smith GH. MMTV-induced mammary tumorigenesis: gene discovery, progression to malignancy and cellular pathways. Oncogene 2000;19 (8):992–1001.

    Article  PubMed  CAS  Google Scholar 

  4. Allan AL, Vantyghem SA, Tuck AB, Chambers AF. Tumor dormancy and cancer stem cells: implications for the biology and treatment of breast cancer metastasis. Breast Dis 2006;26:87–98.

    PubMed  CAS  Google Scholar 

  5. Brackstone M, Townson JL, Chambers AF. Tumour dormancy in breast cancer: an update. Breast Cancer Res 2007;9 (3):208.

    Article  PubMed  CAS  Google Scholar 

  6. Aguirre-Ghiso JA. Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer 2007;7 (11):834–46.

    Article  PubMed  CAS  Google Scholar 

  7. Pao W, Klimstra DS, Fisher GH, Varmus HE. Use of avian retroviral vectors to introduce transcriptional regulators into mammalian cells for analyses of tumor maintenance. Proc Natl Acad Sci U S A 2003;100 (15):8764–9.

    Article  PubMed  CAS  Google Scholar 

  8. Guy CT, Cardiff RD, Muller WJ. Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol Cell Biol 1992;12 (3):954–61.

    PubMed  CAS  Google Scholar 

  9. Lin EY, Jones JG, Li P, Zhu L, Whitney KD, Muller WJ, et al. Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am J Pathol 2003;163 (5):2113–26.

    PubMed  Google Scholar 

  10. Dilworth SM. Polyoma virus middle T antigen and its role in identifying cancer-related molecules. Nat Rev Cancer 2002;2 (12):951–6.

    Article  PubMed  CAS  Google Scholar 

  11. Ichaso N, Dilworth SM. Cell transformation by the middle T-antigen of polyoma virus. Oncogene 2001;20 (54):7908–16.

    Article  PubMed  CAS  Google Scholar 

  12. Ahuja D, Saenz-Robles MT, Pipas JM. SV40 large T antigen targets multiple cellular pathways to elicit cellular transformation. Oncogene 2005;24 (52):7729–45.

    Article  PubMed  CAS  Google Scholar 

  13. Green JE, Shibata MA, Yoshidome K, Liu ML, Jorcyk C, Anver MR, et al. The C3(1)/SV40 T-antigen transgenic mouse model of mammary cancer: ductal epithelial cell targeting with multistage progression to carcinoma. Oncogene 2000;19 (8):1020–7.

    Article  PubMed  CAS  Google Scholar 

  14. Piccart M, Lohrisch C, Di Leo A, Larsimont D. The predictive value of HER2 in breast cancer. Oncology 2001;61 (Suppl 2):73–82.

    Article  PubMed  CAS  Google Scholar 

  15. Lohrisch C, Piccart M. An overview of HER2. Semin Oncol 2001;28 6 (Suppl 18):3–11.

    Article  PubMed  CAS  Google Scholar 

  16. Eccles SA. The role of c-erbB-2/HER2/neu in breast cancer progression and metastasis. J Mammary Gland Biol Neoplasia 2001;6 (4):393–406.

    Article  PubMed  CAS  Google Scholar 

  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 1988;54 (1):105–15.

    Article  PubMed  CAS  Google Scholar 

  18. Bouchard L, Lamarre L, Tremblay PJ, Jolicoeur P. Stochastic appearance of mammary tumors in transgenic mice carrying the MMTV/c-neu oncogene. Cell 1989;57 (6):931–6.

    Article  PubMed  CAS  Google Scholar 

  19. Lemoine NR, Staddon S, Dickson C, Barnes DM, Gullick WJ. Absence of activating transmembrane mutations in the c-erbB-2 proto-oncogene in human breast cancer. Oncogene 1990;5 (2):237–9.

    PubMed  CAS  Google Scholar 

  20. Guy CT, Webster MA, Schaller M, Parsons TJ, Cardiff RD, Muller WJ. Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc Natl Acad Sci U S A 1992;89 (22):10578–82.

    Article  PubMed  CAS  Google Scholar 

  21. Siegel PM, Dankort DL, Hardy WR, Muller WJ. Novel activating mutations in the neu proto-oncogene involved in induction of mammary tumors. Mol Cell Biol 1994;14 (11):7068–77.

    PubMed  CAS  Google Scholar 

  22. Siegel PM, Muller WJ. Mutations affecting conserved cysteine residues within the extracellular domain of Neu promote receptor dimerization and activation. Proc Natl Acad Sci U S A 1996;93 (17):8878–83.

    Article  PubMed  CAS  Google Scholar 

  23. Siegel PM, Ryan ED, Cardiff RD, Muller WJ. 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 1999;18 (8):2149–64.

    Article  PubMed  CAS  Google Scholar 

  24. Kwong KY, Hung MC. A novel splice variant of HER2 with increased transformation activity. Mol Carcinog 1998;23 (2):62–8.

    Article  PubMed  CAS  Google Scholar 

  25. Moody SE, Sarkisian CJ, Hahn KT, Gunther EJ, Pickup S, Dugan KD, et al. Conditional activation of Neu in the mammary epithelium of transgenic mice results in reversible pulmonary metastasis. Cancer Cell 2002;2 (6):451–61.

    Article  PubMed  CAS  Google Scholar 

  26. Moody SE, Perez D, Pan TC, Sarkisian CJ, Portocarrero CP, Sterner CJ, et al. The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell 2005;8 (3):197–209.

    Article  PubMed  CAS  Google Scholar 

  27. Andrechek ER, Hardy WR, Siegel PM, Rudnicki MA, Cardiff RD, Muller WJ. Amplification of the neu/erbB-2 oncogene in a mouse model of mammary tumorigenesis. Proc Natl Acad Sci U S A 2000;97 (7):3444–9.

    Article  PubMed  CAS  Google Scholar 

  28. Montagna C, Andrechek ER, Padilla-Nash H, Muller WJ, Ried T. Centrosome abnormalities, recurring deletions of chromosome 4, and genomic amplification of HER2/neu define mouse mammary gland adenocarcinomas induced by mutant HER2/neu. Oncogene 2002;21 (6):890–8.

    Article  PubMed  CAS  Google Scholar 

  29. Montagna C, Andrechek ER, Padilla-Nash H, Muller WJ, Ried T. Centrosome abnormalities, recurring deletions of chromosome 4, and genomic amplification of HER2/neu define mouse mammary gland adenocarcinomas induced by mutant HER2/neu. Oncogene 2002;21 (6):890–8.

    Article  PubMed  CAS  Google Scholar 

  30. Andrechek ER, Laing MA, Girgis-Gabardo AA, Siegel PM, Cardiff RD, Muller WJ. Gene expression profiling of neu-induced mammary tumors from transgenic mice reveals genetic and morphological similarities to ErbB2-expressing human breast cancers. Cancer Res 2003;63 (16):4920–6.

    PubMed  CAS  Google Scholar 

  31. Gullick WJ. A new model for ductal carcinoma in situ suggests strategies for treatment. Breast Cancer Res 2002;4 (5):176–8.

    Article  PubMed  CAS  Google Scholar 

  32. Tanner MM, Tirkkonen M, Kallioniemi A, Isola J, Kuukasjarvi T, Collins C, et al. Independent amplification and frequent co-amplification of three nonsyntenic regions on the long arm of chromosome 20 in human breast cancer. Cancer Res 1996;56 (15):3441–5.

    PubMed  CAS  Google Scholar 

  33. Wiener JR, Kerns BJ, Harvey EL, Conaway MR, Iglehart JD, Berchuck A, et al. Overexpression of the protein tyrosine phosphatase PTP1B in human breast cancer: association with p185c-erbB-2 protein expression. J Natl Cancer Inst 1994;86 (5):372–8.

    Article  PubMed  CAS  Google Scholar 

  34. Bentires-Alj M, Gil SG, Chan R, Wang ZC, Wang Y, Imanaka N, et al. A role for the scaffolding adapter GAB2 in breast cancer. Nat Med 2006;12 (1):114–21.

    Article  PubMed  CAS  Google Scholar 

  35. Julien SG, Dube N, Read M, Penney J, Paquet M, Han Y, et al. Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2-induced mammary tumorigenesis and protects from lung metastasis. Nat Genet 2007;39 (3):338–46.

    Article  PubMed  CAS  Google Scholar 

  36. Demidov ON, Kek C, Shreeram S, Timofeev O, Fornace AJ, Appella E, et al. The role of the MKK6/p38 MAPK pathway in Wip1-dependent regulation of ErbB2-driven mammary gland tumorigenesis. Oncogene 2007;26 (17):2502–6.

    Article  PubMed  CAS  Google Scholar 

  37. Bulavin DV, Phillips C, Nannenga B, Timofeev O, Donehower LA, Anderson CW, et al. Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK-mediated activation of the p16(Ink4a)–p19(Arf) pathway. Nat Genet 2004;36 (4):343–50.

    Article  PubMed  CAS  Google Scholar 

  38. Muller WJ, Arteaga CL, Muthuswamy SK, Siegel PM, Webster MA, Cardiff RD, et al. Synergistic interaction of the Neu proto-oncogene product and transforming growth factor alpha in the mammary epithelium of transgenic mice. Mol Cell Biol 1996;16 (10):5726–36.

    PubMed  CAS  Google Scholar 

  39. Gillgrass A, Cardiff RD, Sharan N, Kannan S, Muller WJ. Epidermal growth factor receptor-dependent activation of Gab1 is involved in ErbB-2-mediated mammary tumor progression. Oncogene 2003;22 (57):9151–5.

    Article  PubMed  CAS  Google Scholar 

  40. Jackson-Fisher AJ, Bellinger G, Shum E, Duong JK, Perkins AS, Gassmann M, et al. Formation of Neu/ErbB2-induced mammary tumors is unaffected by loss of ErbB4. Oncogene 2006;25:5664–72.

    Article  PubMed  CAS  Google Scholar 

  41. Kim H, Muller WJ. The role of the epidermal growth factor receptor family in mammary tumorigenesis and metastasis. Exp Cell Res 1999;253 (1):78–87.

    Article  PubMed  CAS  Google Scholar 

  42. Guy CT, Muthuswamy SK, Cardiff RD, Soriano P, Muller WJ. Activation of the c-Src tyrosine kinase is required for the induction of mammary tumors in transgenic mice. Genes Dev 1994;8 (1):23–32.

    Article  PubMed  CAS  Google Scholar 

  43. Muthuswamy SK, Siegel PM, Dankort DL, Webster MA, Muller WJ. Mammary tumors expressing the neu proto-oncogene possess elevated c-Src tyrosine kinase activity. Mol Cell Biol 1994;14 (1):735–43.

    PubMed  CAS  Google Scholar 

  44. Muthuswamy SK, Muller WJ. Direct and specific interaction of c-Src with Neu is involved in signaling by the epidermal growth factor receptor. Oncogene 1995;11 (2):271–9.

    PubMed  CAS  Google Scholar 

  45. Kim H, Chan R, Dankort DL, Zuo D, Najoukas M, Park M, et al. The c-Src tyrosine kinase associates with the catalytic domain of ErbB-2: implications for ErbB-2 mediated signaling and transformation. Oncogene 2005;24 (51):7599–607.

    Article  PubMed  CAS  Google Scholar 

  46. Lahlou H, Sanguin-Gendreau V, Zuo D, Cardiff RD, McLean GW, Frame MC, et al. Mammary epithelial-specific disruption of the focal adhesion kinase blocks mammary tumor progression. Proc Natl Acad Sci U S A 2007;104 (51):20302–7.

    Article  PubMed  CAS  Google Scholar 

  47. Hutchinson J, Jin J, Cardiff RD, Woodgett JR, Muller WJ. Activation of Akt (protein kinase B) in mammary epithelium provides a critical cell survival signal required for tumor progression. Mol Cell Biol 2001;21 (6):2203–12.

    Article  PubMed  CAS  Google Scholar 

  48. Hutchinson JN, Jin J, Cardiff RD, Woodgett JR, Muller WJ. Activation of Akt-1 (PKB-alpha) can accelerate ErbB-2-mediated mammary tumorigenesis but suppresses tumor invasion. Cancer Res 2004;64 (9):3171–8.

    Article  PubMed  CAS  Google Scholar 

  49. Irie HY, Pearline RV, Grueneberg D, Hsia M, Ravichandran P, Kothari N, et al. Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial–mesenchymal transition. J Cell Biol 2005;171 (6):1023–34.

    Article  PubMed  CAS  Google Scholar 

  50. Maroulakou IG, Oemler W, Naber SP, Tsichlis PN. Akt1 ablation inhibits, whereas Akt2 ablation accelerates, the development of mammary adenocarcinomas in mouse mammary tumor virus (MMTV)-ErbB2/neu and MMTV-polyoma middle T transgenic mice. Cancer Res 2007;67 (1):167–77.

    Article  PubMed  CAS  Google Scholar 

  51. Ju X, Katiyar S, Wang C, Liu M, Jiao X, Li S, et al. Akt1 governs breast cancer progression in vivo. Proc Natl Acad Sci U S A 2007;104 (18):7438–43.

    Article  PubMed  CAS  Google Scholar 

  52. Pasquale EB. Eph-ephrin bidirectional signaling in physiology and disease. Cell 2008;133 (1):38–52.

    Article  PubMed  CAS  Google Scholar 

  53. Brantley-Sieders DM, Zhuang G, Hicks D, Fang WB, Hwang Y, Cates JM, et al. The receptor tyrosine kinase EphA2 promotes mammary adenocarcinoma tumorigenesis and metastatic progression in mice by amplifying ErbB2 signaling. J Clin Invest 2008;118 (1):64–78.

    Article  PubMed  CAS  Google Scholar 

  54. Daly RJ, Gu H, Parmar J, Malaney S, Lyons RJ, Kairouz R, et al. The docking protein Gab2 is overexpressed and estrogen regulated in human breast cancer. Oncogene 2002;21 (33):5175–81.

    Article  PubMed  CAS  Google Scholar 

  55. Bekri S, Adelaide J, Merscher S, Grosgeorge J, Caroli-Bosc F, Perucca-Lostanlen D, et al. Detailed map of a region commonly amplified at 11q13®q14 in human breast carcinoma. Cytogenet Cell Genet 1997;79 (1–2):125–31.

    Article  PubMed  CAS  Google Scholar 

  56. Ormandy CJ, Musgrove EA, Hui R, Daly RJ, Sutherland RL. Cyclin D1, EMS1 and 11q13 amplification in breast cancer. Breast Cancer Res Treat 2003;78 (3):323–35.

    Article  PubMed  CAS  Google Scholar 

  57. Ke Y, Wu D, Princen F, Nguyen T, Pang Y, Lesperance J, et al. Role of Gab2 in mammary tumorigenesis and metastasis. Oncogene 2007;26 (34):4951–60.

    Article  PubMed  CAS  Google Scholar 

  58. Sakai R, Iwamatsu A, Hirano N, Ogawa S, Tanaka T, Mano H, et al. A novel signaling molecule, p130, forms stable complexes in vivo with v-Crk and v-Src in a tyrosine phosphorylation-dependent manner. Embo J 1994;13 (16):3748–56.

    PubMed  CAS  Google Scholar 

  59. Cabodi S, Tinnirello A, Di Stefano P, Bisaro B, Ambrosino E, Castellano I, et al. p130Cas as a new regulator of mammary epithelial cell proliferation, survival, and HER2-neu oncogene-dependent breast tumorigenesis. Cancer Res 2006;66 (9):4672–80.

    Article  PubMed  CAS  Google Scholar 

  60. Webster MA, Hutchinson JN, Rauh MJ, Muthuswamy SK, Anton M, Tortorice CG, et al. Requirement for both Shc and phosphatidylinositol 3¢ kinase signaling pathways in polyomavirus middle T-mediated mammary tumorigenesis. Mol Cell Biol 1998;18 (4):2344–59.

    PubMed  CAS  Google Scholar 

  61. Rauh MJ, Blackmore V, Andrechek ER, Tortorice CG, Daly R, Lai VK, et al. Accelerated mammary tumor development in mutant polyomavirus middle T transgenic mice expressing elevated levels of either the Shc or Grb2 adapter protein. Mol Cell Biol 1999;19 (12):8169–79.

    PubMed  CAS  Google Scholar 

  62. Cheng AM, Saxton TM, Sakai R, Kulkarni S, Mbamalu G, Vogel W, et al. Mammalian Grb2 regulates multiple steps in embryonic development and malignant transformation. Cell 1998;95 (6):793–803.

    Article  PubMed  CAS  Google Scholar 

  63. Ursini-Siegel J, Hardy WR, Zuo D, Lam SH, Sanguin-Gendreau V, Cardiff RD, et al. ShcA signalling is essential for tumour progression in mouse models of human breast cancer. Embo J 2008;27 (6):910–20.

    Article  PubMed  CAS  Google Scholar 

  64. Dearth RK, Cui X, Kim HJ, Hadsell DL, Lee AV. Oncogenic transformation by the signaling adaptor proteins insulin receptor substrate (IRS)-1 and IRS-2. Cell Cycle 2007;6 (6):705–13.

    PubMed  CAS  Google Scholar 

  65. Hartog H, Wesseling J, Boezen HM, van der Graaf WT. The insulin-like growth factor 1 receptor in cancer: old focus, new future. Eur J Cancer 2007;43 (13):1895–904.

    Article  PubMed  CAS  Google Scholar 

  66. Ma Z, Gibson SL, Byrne MA, Zhang J, White MF, Shaw LM. Suppression of insulin receptor substrate 1 (IRS-1) promotes mammary tumor metastasis. Mol Cell Biol 2006;26 (24):9338–51.

    Article  PubMed  CAS  Google Scholar 

  67. Nagle JA, Ma Z, Byrne MA, White MF, Shaw LM. Involvement of insulin receptor substrate 2 in mammary tumor metastasis. Mol Cell Biol 2004;24 (22):9726–35.

    Article  PubMed  CAS  Google Scholar 

  68. Mariotti A, Kedeshian PA, Dans M, Curatola AM, Gagnoux-Palacios L, Giancotti FG. EGF-R signaling through Fyn kinase disrupts the function of integrin alpha6beta4 at hemidesmosomes: role in epithelial cell migration and carcinoma invasion. J Cell Biol 2001;155 (3):447–58.

    Article  PubMed  CAS  Google Scholar 

  69. Morini M, Mottolese M, Ferrari N, Ghiorzo F, Buglioni S, Mortarini R, et al. The alpha 3 beta 1 integrin is associated with mammary carcinoma cell metastasis, invasion, and gelatinase B (MMP-9) activity. Int J Cancer 2000;87 (3):336–42.

    Article  PubMed  CAS  Google Scholar 

  70. Moro L, Venturino M, Bozzo C, Silengo L, Altruda F, Beguinot L, et al. Integrins induce activation of EGF receptor: role in MAP kinase induction and adhesion-dependent cell survival. Embo J 1998;17 (22):6622–32.

    Article  PubMed  CAS  Google Scholar 

  71. Weaver VM, Petersen OW, Wang F, Larabell CA, Briand P, Damsky C, et al. Reversion of the malignant phenotype of human breast cells in three-dimensional culture and in vivo by integrin blocking antibodies. J Cell Biol 1997;137 (1):231–45.

    Article  PubMed  CAS  Google Scholar 

  72. Adelsman MA, McCarthy JB, Shimizu Y. Stimulation of beta1-integrin function by epidermal growth factor and heregulin-beta has distinct requirements for erbB2 but a similar dependence on phosphoinositide 3-OH kinase. Mol Biol Cell 1999;10 (9):2861–78.

    PubMed  CAS  Google Scholar 

  73. Wang F, Hansen RK, Radisky D, Yoneda T, Barcellos-Hoff MH, Petersen OW, et al. Phenotypic reversion or death of cancer cells by altering signaling pathways in three-dimensional contexts. J Natl Cancer Inst 2002;94 (19):1494–503.

    PubMed  CAS  Google Scholar 

  74. White DE, Kurpios NA, Zuo D, Hassell JA, Blaess S, Mueller U, et al. Targeted disruption of beta1-integrin in a transgenic mouse model of human breast cancer reveals an essential role in mammary tumor induction. Cancer Cell 2004;6 (2):159–70.

    Article  PubMed  CAS  Google Scholar 

  75. Li N, Zhang Y, Naylor MJ, Schatzmann F, Maurer F, Wintermantel T, et al. Beta1 integrins regulate mammary gland proliferation and maintain the integrity of mammary alveoli. Embo J 2005;24 (11):1942–53.

    Article  PubMed  CAS  Google Scholar 

  76. Aguirre Ghiso JA, Kovalski K, Ossowski L. Tumor dormancy induced by downregulation of urokinase receptor in human carcinoma involves integrin and MAPK signaling. J Cell Biol 1999;147 (1):89–104.

    Article  PubMed  CAS  Google Scholar 

  77. Aguirre Ghiso JA. Inhibition of FAK signaling activated by urokinase receptor induces dormancy in human carcinoma cells in vivo. Oncogene 2002;21 (16):2513–24.

    Article  PubMed  Google Scholar 

  78. Guo W, Pylayeva Y, Pepe A, Yoshioka T, Muller WJ, Inghirami G, et al. Beta 4 integrin amplifies ErbB2 signaling to promote mammary tumorigenesis. Cell 2006;126 (3):489–502.

    Article  PubMed  CAS  Google Scholar 

  79. Taverna D, Crowley D, Connolly M, Bronson RT, Hynes RO. A direct test of potential roles for beta3 and beta5 integrins in growth and metastasis of murine mammary carcinomas. Cancer Res 2005;65 (22):10324–9.

    Article  PubMed  CAS  Google Scholar 

  80. Besson A, Dowdy SF, Roberts JM. CDK inhibitors: cell cycle regulators and beyond. Dev Cell 2008;14 (2):159–69.

    Article  PubMed  CAS  Google Scholar 

  81. Roy PG, Thompson AM. Cyclin D1 and breast cancer. Breast 2006;15 (6):718–27.

    Article  PubMed  Google Scholar 

  82. Wang TC, Cardiff RD, Zukerberg L, Lees E, Arnold A, Schmidt EV. Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice. Nature 1994;369 (6482):669–71.

    Article  PubMed  CAS  Google Scholar 

  83. Yu Q, Geng Y, Sicinski P. Specific protection against breast cancers by cyclin D1 ablation. Nature 2001;411 (6841):1017–21.

    Article  PubMed  CAS  Google Scholar 

  84. Landis MW, Pawlyk BS, Li T, Sicinski P, Hinds PW. Cyclin D1-dependent kinase activity in murine development and mammary tumorigenesis. Cancer Cell 2006;9 (1):13–22.

    Article  PubMed  CAS  Google Scholar 

  85. Cao Y, Bonizzi G, Seagroves TN, Greten FR, Johnson R, Schmidt EV, et al. IKKalpha provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development. Cell 2001;107 (6):763–75.

    Article  PubMed  CAS  Google Scholar 

  86. Cao Y, Luo JL, Karin M. IkappaB kinase alpha kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells. Proc Natl Acad Sci U S A 2007;104 (40):15852–7.

    Article  PubMed  CAS  Google Scholar 

  87. Sicinski P, Zacharek S, Kim C. Duality of p27Kip1 function in tumorigenesis. Genes Dev 2007;21 (14):1703–6.

    Article  PubMed  CAS  Google Scholar 

  88. Hulit J, Lee RJ, Li Z, Wang C, Katiyar S, Yang J, et al. p27Kip1 repression of ErbB2-induced mammary tumor growth in transgenic mice involves Skp2 and Wnt/beta-catenin signaling. Cancer Res 2006;66 (17):8529–41.

    Article  PubMed  CAS  Google Scholar 

  89. Muraoka RS, Lenferink AE, Law B, Hamilton E, Brantley DM, Roebuck LR, et al. ErbB2/Neu-induced, cyclin D1-dependent transformation is accelerated in p27-haploinsufficient mammary epithelial cells but impaired in p27-null cells. Mol Cell Biol 2002;22 (7):2204–19.

    Article  PubMed  CAS  Google Scholar 

  90. Besson A, Hwang HC, Cicero S, Donovan SL, Gurian-West M, Johnson D, et al. Discovery of an oncogenic activity in p27Kip1 that causes stem cell expansion and a multiple tumor phenotype. Genes Dev 2007;21 (14):1731–46.

    Article  PubMed  CAS  Google Scholar 

  91. D’Amico M, Wu K, Di Vizio D, Reutens AT, Stahl M, Fu M, et al. The role of Ink4a/Arf in ErbB2 mammary gland tumorigenesis. Cancer Res 2003;63 (12):3395–402.

    PubMed  CAS  Google Scholar 

  92. Ma ZQ, Chua SS, DeMayo FJ, Tsai SY. Induction of mammary gland hyperplasia in transgenic mice over-expressing human Cdc25B. Oncogene 1999;18 (32):4564–76.

    Article  PubMed  CAS  Google Scholar 

  93. Yao Y, Slosberg ED, Wang L, Hibshoosh H, Zhang YJ, Xing WQ, et al. Increased susceptibility to carcinogen-induced mammary tumors in MMTV-Cdc25B transgenic mice. Oncogene 1999;18 (37):5159–66.

    Article  PubMed  CAS  Google Scholar 

  94. Ray D, Terao Y, Nimbalkar D, Hirai H, Osmundson EC, Zou X, et al. Hemizygous disruption of Cdc25A inhibits cellular transformation and mammary tumorigenesis in mice. Cancer Res 2007;67 (14):6605–11.

    Article  PubMed  CAS  Google Scholar 

  95. Greenlee KJ, Werb Z, Kheradmand F. Matrix metalloproteinases in lung: multiple, multifarious, and multifaceted. Physiol Rev 2007;87 (1):69–98.

    Article  PubMed  CAS  Google Scholar 

  96. Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2002;2 (3):161–74.

    Article  PubMed  CAS  Google Scholar 

  97. Ha HY, Moon HB, Nam MS, Lee JW, Ryoo ZY, Lee TH, et al. Overexpression of membrane-type matrix metalloproteinase-1 gene induces mammary gland abnormalities and adenocarcinoma in transgenic mice. Cancer Res 2001;61 (3):984–90.

    PubMed  CAS  Google Scholar 

  98. Sternlicht MD, Lochter A, Sympson CJ, Huey B, Rougier JP, Gray JW, et al. The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell 1999;98 (2):137–46.

    Article  PubMed  CAS  Google Scholar 

  99. Sternlicht MD, Bissell MJ, Werb Z. The matrix metalloproteinase stromelysin-1 acts as a natural mammary tumor promoter. Oncogene 2000;19 (8):1102–13.

    Article  PubMed  CAS  Google Scholar 

  100. Rudolph-Owen LA, Chan R, Muller WJ, Matrisian LM. The matrix metalloproteinase matrilysin influences early-stage mammary tumorigenesis. Cancer Res 1998;58 (23):5500–6.

    PubMed  CAS  Google Scholar 

  101. Szabova L, Chrysovergis K, Yamada SS, Holmbeck K. MT1-MMP is required for efficient tumor dissemination in experimental metastatic disease. Oncogene 2007;27 (23):3274–81.

    Article  PubMed  CAS  Google Scholar 

  102. Vasiljeva O, Papazoglou A, Kruger A, Brodoefel H, Korovin M, Deussing J, et al. Tumor cell-derived and macrophage-derived cathepsin B promotes progression and lung metastasis of mammary cancer. Cancer Res 2006;66 (10):5242–50.

    Article  PubMed  CAS  Google Scholar 

  103. Poole AR, Tiltman KJ, Recklies AD, Stoker TA. Differences in secretion of the proteinase cathepsin B at the edges of human breast carcinomas and fibroadenomas. Nature 1978;273 (5663):545–7.

    Article  PubMed  CAS  Google Scholar 

  104. Yamazaki M, Akahane T, Buck T, Yoshiji H, Gomez DE, Schoeffner DJ, et al. Long-term exposure to elevated levels of circulating TIMP-1 but not mammary TIMP-1 suppresses growth of mammary carcinomas in transgenic mice. Carcinogenesis 2004;25 (9):1735–46.

    Article  PubMed  CAS  Google Scholar 

  105. Sidenius N, Blasi F. The urokinase plasminogen activator system in cancer: recent advances and implication for prognosis and therapy. Cancer Metastasis Rev 2003;22 (2–3):205–22.

    Article  PubMed  CAS  Google Scholar 

  106. Bugge TH, Lund LR, Kombrinck KK, Nielsen BS, Holmback K, Drew AF, et al. Reduced metastasis of polyoma virus middle T antigen-induced mammary cancer in plasminogen-deficient mice. Oncogene 1998;16 (24):3097–104.

    Article  PubMed  CAS  Google Scholar 

  107. Almholt K, Lund LR, Rygaard J, Nielsen BS, Dano K, Romer J, et al. Reduced metastasis of transgenic mammary cancer in urokinase-deficient mice. Int J Cancer 2005;113 (4):525–32.

    Article  PubMed  CAS  Google Scholar 

  108. Pierce DF Jr, Johnson MD, Matsui Y, Robinson SD, Gold LI, Purchio AF, et al. Inhibition of mammary duct development but not alveolar outgrowth during pregnancy in transgenic mice expressing active TGF-beta 1. Genes Dev 1993;7 (12A):2308–17.

    Article  PubMed  CAS  Google Scholar 

  109. Pierce DF Jr, Gorska AE, Chytil A, Meise KS, Page DL, Coffey RJ Jr, et al. Mammary tumor suppression by transforming growth factor beta 1 transgene expression. Proc Natl Acad Sci U S A 1995;92 (10):4254–8.

    Article  PubMed  CAS  Google Scholar 

  110. Bottinger EP, Jakubczak JL, Haines DC, Bagnall K, Wakefield LM. Transgenic mice overexpressing a dominant-negative mutant type II transforming growth factor beta receptor show enhanced tumorigenesis in the mammary gland and lung in response to the carcinogen 7,12-dimethylbenz-[a]-anthracene. Cancer Res 1997;57 (24):5564–70.

    PubMed  CAS  Google Scholar 

  111. Gorska AE, Jensen RA, Shyr Y, Aakre ME, Bhowmick NA, Moses HL. Transgenic mice expressing a dominant-negative mutant type II transforming growth factor-beta receptor exhibit impaired mammary development and enhanced mammary tumor formation. Am J Pathol 2003;163 (4):1539–49.

    PubMed  CAS  Google Scholar 

  112. Forrester E, Chytil A, Bierie B, Aakre M, Gorska AE, Sharif-Afshar AR, et al. Effect of conditional knockout of the type II TGF-beta receptor gene in mammary epithelia on mammary gland development and polyomavirus middle T antigen induced tumor formation and metastasis. Cancer Res 2005;65 (6):2296–302.

    Article  PubMed  CAS  Google Scholar 

  113. Siegel PM, Shu W, Cardiff RD, Muller WJ, Massague J. Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Proc Natl Acad Sci U S A 2003;100 (14):8430–5.

    Article  PubMed  CAS  Google Scholar 

  114. Muraoka-Cook RS, Shin I, Yi JY, Easterly E, Barcellos-Hoff MH, Yingling JM, et al. Activated type I TGFbeta receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression. Oncogene 2006;25 (24):3408–23.

    Article  PubMed  CAS  Google Scholar 

  115. Muraoka RS, Koh Y, Roebuck LR, Sanders ME, Brantley-Sieders D, Gorska AE, et al. Increased malignancy of Neu-induced mammary tumors overexpressing active transforming growth factor beta1. Mol Cell Biol 2003;23 (23):8691–703.

    Article  PubMed  CAS  Google Scholar 

  116. Walker RA, Dearing SJ. Transforming growth factor beta 1 in ductal carcinoma in situ and invasive carcinomas of the breast. Eur J Cancer 1992;28 (2–3):641–4.

    Article  PubMed  CAS  Google Scholar 

  117. Gorsch SM, Memoli VA, Stukel TA, Gold LI, Arrick BA. Immunohistochemical staining for transforming growth factor beta 1 associates with disease progression in human breast cancer. Cancer Res 1992;52 (24):6949–52.

    PubMed  CAS  Google Scholar 

  118. Muraoka-Cook RS, Kurokawa H, Koh Y, Forbes JT, Roebuck LR, Barcellos-Hoff MH, et al. Conditional overexpression of active transforming growth factor beta1 in vivo accelerates metastases of transgenic mammary tumors. Cancer Res 2004;64 (24):9002–11.

    Article  PubMed  CAS  Google Scholar 

  119. Coles C, Condie A, Chetty U, Steel CM, Evans HJ, Prosser J. p53 mutations in breast cancer. Cancer Res 1992;52 (19):5291–8.

    PubMed  CAS  Google Scholar 

  120. Blackburn AC, Jerry DJ. Knockout and transgenic mice of Trp53: what have we learned about p53 in breast cancer. Breast Cancer Res 2002;4 (3):101–11.

    Article  PubMed  CAS  Google Scholar 

  121. Li B, Rosen JM, McMenamin-Balano J, Muller WJ, Perkins AS. neu/ERBB2 cooperates with p53-172H during mammary tumorigenesis in transgenic mice. Mol Cell Biol 1997;17 (6):3155–63.

    PubMed  CAS  Google Scholar 

  122. Li G, Robinson GW, Lesche R, Martinez-Diaz H, Jiang Z, Rozengurt N, et al. Conditional loss of PTEN leads to precocious development and neoplasia in the mammary gland. Development 2002;129 (17):4159–70.

    PubMed  CAS  Google Scholar 

  123. Dourdin N, Schade B, Lesurf R, Hallett M, Munn RJ, Cardiff RD, et al. Phosphatase and tensin homologue deleted on chromosome 10 deficiency accelerates tumor induction in a mouse model of ErbB-2 mammary tumorigenesis. Cancer Res 2008;68 (7):2122–31.

    Article  PubMed  CAS  Google Scholar 

  124. Herschkowitz JI, Simin K, Weigman VJ, Mikaelian I, Usary J, Hu Z, et al. Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol 2007;8 (5):R76.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgement

The authors would like to thank Rachelle Dillon for proofreading the manuscript. This work was supported by grants from NIH PO1, Terry Fox Group grant, CBCRA, CIHR, DOD and CRS.

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  1. Molecular Oncology Group, Royal Victoria Hospital, room H5.21, 687 Pine Avenue West, Montreal, QC, Canada, H3A 1A1

    Richard Marcotte & William J. Muller

  2. Department of Biochemistry, McGill University, Montreal, Canada

    Richard Marcotte & William J. Muller

  3. Department of Medicine, McGill University, Montreal, Canada

    William J. Muller

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Marcotte, R., Muller, W.J. Signal Transduction in Transgenic Mouse Models of Human Breast Cancer—Implications for Human Breast Cancer. J Mammary Gland Biol Neoplasia 13, 323–335 (2008). https://doi.org/10.1007/s10911-008-9087-3

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  • DOI: https://doi.org/10.1007/s10911-008-9087-3

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