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Mouse Models of Breast Cancer: Deceptions that Reveal the Truth

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Abstract

Breast cancer is the most frequently diagnosed malignancy and results in the highest cancer mortality in women aged 20–59 years worldwide [1]. The disease usually progresses from hyperplasia to ductal carcinoma in situ (DCIS), and subsequently invasive carcinoma and metastasis, the latter accounting for almost all deaths among these patients [2].

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References

  1. World Cancer Report 2014 (2014) International agency for research on cancer—WHO

    Google Scholar 

  2. Bombonati A, Sgroi DC (2011) The molecular pathology of breast cancer progression. J Pathol 223(2):307–317

    Article  CAS  PubMed  Google Scholar 

  3. Viale G (2012) The current state of breast cancer classification. Ann Oncol 23(Suppl 10):x207–x210

    Article  PubMed  Google Scholar 

  4. Perou CM et al (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752

    Article  CAS  PubMed  Google Scholar 

  5. van’t Veer LJ et al (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415(6871):530–536

    Article  Google Scholar 

  6. Herschkowitz JI et al (2007) Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol 8(5):R76

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Sorlie T et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98(19):10869–10874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sorlie T et al (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 100(14):8418–8423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Prat A et al (2010) Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res 12(5):R68

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Santagata S et al (2014) Taxonomy of breast cancer based on normal cell phenotype predicts outcome. J Clin Invest 124(2):859–870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Troester MA et al (2004) Cell-type-specific responses to chemotherapeutics in breast cancer. Cancer Res 64(12):4218–4226

    Article  CAS  PubMed  Google Scholar 

  12. Curtis C et al (2012) The genomic and transcriptomic architecture of 2000 breast tumours reveals novel subgroups. Nature 486(7403):346–352

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Banerji S et al (2012) Sequence analysis of mutations and translocations across breast cancer subtypes. Nature 486(7403):405–409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Stephens PJ et al (2012) The landscape of cancer genes and mutational processes in breast cancer. Nature 486(7403):400–404

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Ellis MJ et al (2012) Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature 486(7403):353–360

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Shah SP et al (2012) The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 486(7403):395–399

    CAS  PubMed  Google Scholar 

  17. Goncalves R et al (2014) New concepts in breast cancer genomics and genetics. Breast Cancer Res 16(5):460

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Bedard PL et al (2013) Tumour heterogeneity in the clinic. Nature 501(7467):355–364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gould SE, Junttila MR, de Sauvage FJ (2015) Translational value of mouse models in oncology drug development. Nat Med 21(5):431–439

    Article  CAS  PubMed  Google Scholar 

  20. Medina D (2010) Of mice and women: a short history of mouse mammary cancer research with an emphasis on the paradigms inspired by the transplantation method. Cold Spring Harb Perspect Biol 2(10):a004523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cardiff RD, Kenney N (2011) A compendium of the mouse mammary tumor biologist: from the initial observations in the house mouse to the development of genetically engineered mice. Cold Spring Harb Perspect Biol 3(6):a003111

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Taneja P et al (2009) MMTV mouse models and the diagnostic values of MMTV-like sequences in human breast cancer. Expert Rev Mol Diagn 9(5):423–440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 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(1):99–109

    Article  CAS  PubMed  Google Scholar 

  24. Nusse R (1991) Insertional mutagenesis in mouse mammary tumorigenesis. Curr Top Microbiol Immunol 171:43–65

    CAS  PubMed  Google Scholar 

  25. Jhappan C et al (1992) Expression of an activated notch-related int-3 transgene interferes with cell differentiation and induces neoplastic transformation in mammary and salivary glands. Genes Dev 6(3):345–355

    Article  CAS  PubMed  Google Scholar 

  26. Callahan R, Smith GH (2008) Common integration sites for MMTV in viral induced mouse mammary tumors. J Mammary Gland Biol Neoplasia 13(3):309–321

    Article  PubMed  PubMed Central  Google Scholar 

  27. Mukhopadhyay R et al (2010) Promotion of variant human mammary epithelial cell outgrowth by ionizing radiation: an agent-based model supported by in vitro studies. Breast Cancer Res 12(1):R11

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Yaffe MJ, Mainprize JG (2011) Risk of radiation-induced breast cancer from mammographic screening. Radiology 258(1):98–105

    Article  PubMed  Google Scholar 

  29. Beatson GT (1896) On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment, with illustrated cases. Lancet 2:104–107. 162–165

    Article  Google Scholar 

  30. Lacassagne A (1932) Apparition de cancers de la mammelle chez la souris male, soumis a des injections de folliculine. CR Acad Sci 195:630–632

    Google Scholar 

  31. Arendt LM et al (2011) Prolactin-induced mouse mammary carcinomas model estrogen resistant luminal breast cancer. Breast Cancer Res 13(1):R11

    Article  PubMed  PubMed Central  Google Scholar 

  32. Vinay DS et al (2015) Immune evasion in cancer: mechanistic basis and therapeutic strategies. Semin Cancer Biol 35:S185–S198

    Article  PubMed  CAS  Google Scholar 

  33. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674

    Article  CAS  PubMed  Google Scholar 

  34. Valastyan S, Weinberg RA (2011) Tumor metastasis: molecular insights and evolving paradigms. Cell 147(2):275–292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Shibue T, Weinberg RA (2011) Metastatic colonization: settlement, adaptation and propagation of tumor cells in a foreign tissue environment. Semin Cancer Biol 21(2):99–106

    Article  CAS  PubMed  Google Scholar 

  36. Mestas J, Hughes CC (2004) Of mice and not men: differences between mouse and human immunology. J Immunol 172(5):2731–2738

    Article  CAS  PubMed  Google Scholar 

  37. Ito R et al (2012) Current advances in humanized mouse models. Cell Mol Immunol 9(3):208–214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Khanna C, Hunter K (2005) Modeling metastasis in vivo. Carcinogenesis 26(3):513–523

    Article  CAS  PubMed  Google Scholar 

  39. Strong LC (1935) The establishment of the C(3)H inbred strain of mice for the study of spontaneous carcinoma of the mammary gland. Genetics 20(6):586–591

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Deome KB et al (1959) Development of mammary tumors from hyperplastic alveolar nodules transplanted into gland-free mammary fat pads of female C3H mice. Cancer Res 19(5):515–520

    CAS  PubMed  Google Scholar 

  41. Jerry DJ et al (2000) A mammary-specific model demonstrates the role of the p53 tumor suppressor gene in tumor development. Oncogene 19(8):1052–1058

    Google Scholar 

  42. Kuperwasser C et al (2000) Development of spontaneous mammary tumors in BALB/c p53 heterozygous mice. A model for Li-Fraumeni syndrome. Am J Pathol 157(6):2151–2159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Behbod F et al (2009) An intraductal human-in-mouse transplantation model mimics the subtypes of ductal carcinoma in situ. Breast Cancer Res 11(5):R66

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Medina D et al (2012) Intra-mammary ductal transplantation: a tool to study premalignant progression. J Mammary Gland Biol Neoplasia 17(2):131–133

    Article  PubMed  Google Scholar 

  45. Britschgi A et al (2012) JAK2/STAT5 inhibition circumvents resistance to PI3K/mTOR blockade: a rationale for cotargeting these pathways in metastatic breast cancer. Cancer Cell 22(6):796–811

    Article  CAS  PubMed  Google Scholar 

  46. Bonapace L et al (2014) Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis. Nature 515(7525):130–133

    Article  CAS  PubMed  Google Scholar 

  47. Saxena M, Christofori G (2013) Rebuilding cancer metastasis in the mouse. Mol Oncol 7(2):283–296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Aceto N et al (2014) Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 158(5):1110–1122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kang Y et al (2003) A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3(6):537–549

    Article  CAS  PubMed  Google Scholar 

  50. Minn AJ et al (2005) Genes that mediate breast cancer metastasis to lung. Nature 436(7050):518–524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kang Y et al (2005) Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. Proc Natl Acad Sci USA 102(39):13909–13914

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Gupta GP et al (2007) Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature 446(7137):765–770

    Article  CAS  PubMed  Google Scholar 

  53. Bos PD et al (2009) Genes that mediate breast cancer metastasis to the brain. Nature 459(7249):1005–1009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Lu X et al (2011) VCAM-1 promotes osteolytic expansion of indolent bone micrometastasis of breast cancer by engaging alpha4beta1-positive osteoclast progenitors. Cancer Cell 20(6):701–714

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ellis LM, Fidler IJ (2010) Finding the tumor copycat. Therapy fails, patients don’t. Nat Med 16(9):974–975

    Article  CAS  PubMed  Google Scholar 

  56. Gillet JP et al (2011) Redefining the relevance of established cancer cell lines to the study of mechanisms of clinical anti-cancer drug resistance. Proc Natl Acad Sci USA 108(46):18708–18713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Brooks MD, Burness ML, Wicha MS (2015) Therapeutic implications of cellular heterogeneity and plasticity in breast cancer. Cell Stem Cell 17(3):260–271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Koren S, Bentires-Alj M (2015) Breast Tumor Heterogeneity: Source of Fitness, Hurdle for Therapy. Mol Cell 60(4):537–546

    Google Scholar 

  59. Tentler JJ et al (2012) Patient-derived tumour xenografts as models for oncology drug development. Nat Rev Clin Oncol 9(6):338–350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Whittle JR et al (2015) Patient-derived xenograft models of breast cancer and their predictive power. Breast Cancer Res 17:17

    Article  PubMed  PubMed Central  Google Scholar 

  61. Gao H et al (2015) High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response. Nat Med 21(11):1318–1325

    Article  CAS  PubMed  Google Scholar 

  62. Reyal F et al (2012) Molecular profiling of patient-derived breast cancer xenografts. Breast Cancer Res 14(1):R11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhang X et al (2013) A renewable tissue resource of phenotypically stable, biologically and ethnically diverse, patient-derived human breast cancer xenograft models. Cancer Res 73(15):4885–4897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. DeRose YS et al (2013) Patient-derived models of human breast cancer: protocols for in vitro and in vivo applications in tumor biology and translational medicine. Curr Protoc Pharmacol Chapter 14:Unit14 23

    PubMed  Google Scholar 

  65. Aparicio S, Hidalgo M, Kung AL (2015) Examining the utility of patient-derived xenograft mouse models. Nat Rev Cancer 15(5):311–316

    Article  CAS  PubMed  Google Scholar 

  66. Eirew P et al (2015) Dynamics of genomic clones in breast cancer patient xenografts at single-cell resolution. Nature 518(7539):422–426

    Article  CAS  PubMed  Google Scholar 

  67. Ding L et al (2010) Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature 464(7291):999–1005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. DeRose YS et al (2011) Tumor grafts derived from women with breast cancer authentically reflect tumor pathology, growth, metastasis and disease outcomes. Nat Med 17(11):1514–1520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Fridman R et al (2012) Increased initiation and growth of tumor cell lines, cancer stem cells and biopsy material in mice using basement membrane matrix protein (Cultrex or Matrigel) co-injection. Nat Protoc 7(6):1138–1144

    Article  CAS  PubMed  Google Scholar 

  70. Kuperwasser C et al (2004) Reconstruction of functionally normal and malignant human breast tissues in mice. Proc Natl Acad Sci USA 101(14):4966–4971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kuperwasser C et al (2005) A mouse model of human breast cancer metastasis to human bone. Cancer Res 65(14):6130–6138

    Article  CAS  PubMed  Google Scholar 

  72. Shultz LD, Ishikawa F, Greiner DL (2007) Humanized mice in translational biomedical research. Nat Rev Immunol 7(2):118–130

    Article  CAS  PubMed  Google Scholar 

  73. Brehm MA, Shultz LD (2012) Human allograft rejection in humanized mice: a historical perspective. Cell Mol Immunol 9(3):225–231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Shultz LD et al (2010) Generation of functional human T-cell subsets with HLA-restricted immune responses in HLA class I expressing NOD/SCID/IL2r gamma(null) humanized mice. Proc Natl Acad Sci USA 107(29):13022–13027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Shultz LD et al (2012) Humanized mice for immune system investigation: progress, promise and challenges. Nat Rev Immunol 12(11):786–798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Katano I et al (2015) Predominant development of mature and functional human NK cells in a novel human IL-2-producing transgenic NOG mouse. J Immunol 194(7):3513–3525

    Article  CAS  PubMed  Google Scholar 

  77. Willinger T et al (2011) Human IL-3/GM-CSF knock-in mice support human alveolar macrophage development and human immune responses in the lung. Proc Natl Acad Sci USA 108(6):2390–2395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. van Lent AU et al (2009) IL-7 enhances thymic human T cell development in “human immune system” Rag2−/−IL-2Rgammac−/− mice without affecting peripheral T cell homeostasis. J Immunol 183(12):7645–7655

    Article  PubMed  CAS  Google Scholar 

  79. Rongvaux A et al (2011) Human thrombopoietin knockin mice efficiently support human hematopoiesis in vivo. Proc Natl Acad Sci USA 108(6):2378–2383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Rongvaux A et al (2014) Development and function of human innate immune cells in a humanized mouse model. Nat Biotechnol 32(4):364–372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Dontu G, Ince TA (2015) Of mice and women: a comparative tissue biology perspective of breast stem cells and differentiation. J Mammary Gland Biol Neoplasia 20(1–2):51–62

    Article  PubMed  PubMed Central  Google Scholar 

  82. Lewandoski M (2001) Conditional control of gene expression in the mouse. Nat Rev Genet 2(10):743–755

    Article  CAS  PubMed  Google Scholar 

  83. Jonkers J, Berns A (2002) Conditional mouse models of sporadic cancer. Nat Rev Cancer 2(4):251–265

    Article  CAS  PubMed  Google Scholar 

  84. Vasioukhin V et al (1999) The magical touch: genome targeting in epidermal stem cells induced by tamoxifen application to mouse skin. Proc Natl Acad Sci USA 96(15):8551–8556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Gunther EJ et al (2002) A novel doxycycline-inducible system for the transgenic analysis of mammary gland biology. FASEB J 16(3):283–292

    Article  CAS  PubMed  Google Scholar 

  86. Sun Y, Chen X, Xiao D (2007) Tetracycline-inducible expression systems: new strategies and practices in the transgenic mouse modeling. Acta Biochim Biophys Sin (Shanghai) 39(4):235–246

    Article  CAS  Google Scholar 

  87. Jonkers J et al (2001) Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nat Genet 29(4):418–425

    Article  CAS  PubMed  Google Scholar 

  88. Van Keymeulen A et al (2011) Distinct stem cells contribute to mammary gland development and maintenance. Nature 479(7372):189–193

    Article  PubMed  CAS  Google Scholar 

  89. Koren S et al (2015) PIK3CA(H1047R) induces multipotency and multi-lineage mammary tumours. Nature 525(7567):114–118

    Article  CAS  PubMed  Google Scholar 

  90. Van Keymeulen A et al (2015) Reactivation of multipotency by oncogenic PIK3CA induces breast tumour heterogeneity. Nature 525(7567):119–123

    Article  PubMed  CAS  Google Scholar 

  91. Weinstein IB, Joe AK (2006) Mechanisms of disease: oncogene addiction—a rationale for molecular targeting in cancer therapy. Nat Clin Pract Oncol 3(8):448–457

    Article  CAS  PubMed  Google Scholar 

  92. Balavenkatraman KK et al (2011) Epithelial protein-tyrosine phosphatase 1B contributes to the induction of mammary tumors by HER2/Neu but is not essential for tumor maintenance. Mol Cancer Res 9(10):1377–1384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Wagner KU et al (2001) Spatial and temporal expression of the Cre gene under the control of the MMTV-LTR in different lines of transgenic mice. Transgenic Res 10(6):545–553

    Article  CAS  PubMed  Google Scholar 

  94. Pittius CW et al (1988) A milk protein gene promoter directs the expression of human tissue plasminogen activator cDNA to the mammary gland in transgenic mice. Proc Natl Acad Sci USA 85(16):5874–5878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Evers B, Jonkers J (2006) Mouse models of BRCA1 and BRCA2 deficiency: past lessons, current understanding and future prospects. Oncogene 25(43):5885–5897

    Article  CAS  PubMed  Google Scholar 

  96. Simin K et al (2004) pRb inactivation in mammary cells reveals common mechanisms for tumor initiation and progression in divergent epithelia. PLoS Biol 2(2):E22

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Schulze-Garg C et al (2000) A transgenic mouse model for the ductal carcinoma in situ (DCIS) of the mammary gland. Oncogene 19(8):1028–1037

    Article  CAS  PubMed  Google Scholar 

  98. Meyer DS et al (2013) Expression of PIK3CA mutant E545K in the mammary gland induces heterogeneous tumors but is less potent than mutant H1047R. Oncogenesis 2:e74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Rios AC et al (2014) In situ identification of bipotent stem cells in the mammary gland. Nature 506(7488):322–327

    Article  CAS  PubMed  Google Scholar 

  100. Liu X et al (2007) Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer. Proc Natl Acad Sci USA 104(29):12111–12116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Teuliere J et al (2005) Targeted activation of beta-catenin signaling in basal mammary epithelial cells affects mammary development and leads to hyperplasia. Development 132(2):267–277

    Article  CAS  PubMed  Google Scholar 

  102. Barker N et al (2007) Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449(7165):1003–1007

    Article  CAS  PubMed  Google Scholar 

  103. Barker N et al (2010) Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell 6(1):25–36

    Article  CAS  PubMed  Google Scholar 

  104. Barker N et al (2008) Very long-term self-renewal of small intestine, colon, and hair follicles from cycling Lgr5+ve stem cells. Cold Spring Harb Symp Quant Biol 73:351–356

    Article  CAS  PubMed  Google Scholar 

  105. Plaks V et al (2013) Lgr5-expressing cells are sufficient and necessary for postnatal mammary gland organogenesis. Cell Rep 3(1):70–78

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Green JE et al (2000) The C3(1)/SV40 T-antigen transgenic mouse model of mammary cancer: ductal epithelial cell targeting with multistage progression to carcinoma. Oncogene 19(8):1020–1027

    Article  CAS  PubMed  Google Scholar 

  107. Turksen K et al (1992) Interleukin 6: insights to its function in skin by overexpression in transgenic mice. Proc Natl Acad Sci USA 89(11):5068–5072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Whitelaw CB et al (1992) Position-independent expression of the ovine beta-lactoglobulin gene in transgenic mice. Biochem J 286(Pt 1):31–39

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Molyneux G et al (2010) BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell 7(3):403–417

    Article  CAS  PubMed  Google Scholar 

  110. Melchor L et al (2014) Identification of cellular and genetic drivers of breast cancer heterogeneity in genetically engineered mouse tumour models. J Pathol 233(2):124–137

    Article  CAS  PubMed  Google Scholar 

  111. Palmiter RD et al (1993) Distal regulatory elements from the mouse metallothionein locus stimulate gene expression in transgenic mice. Mol Cell Biol 13(9):5266–5275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Liang TJ et al (1996) Transgenic expression of tpr-met oncogene leads to development of mammary hyperplasia and tumors. J Clin Invest 97(12):2872–2877

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Jeffers M et al (1998) The mutationally activated Met receptor mediates motility and metastasis. Proc Natl Acad Sci USA 95(24):14417–14422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Tomblyn S et al (2005) The role of human prolactin and its antagonist, G129R, in mammary gland development and DMBA-initiated tumorigenesis in transgenic mice. Int J Oncol 27(5):1381–1389

    CAS  PubMed  Google Scholar 

  115. Futreal PA et al (1994) BRCA1 mutations in primary breast and ovarian carcinomas. Science 266(5182):120–122

    Article  CAS  PubMed  Google Scholar 

  116. Miki Y et al (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266(5182):66–71

    Article  CAS  PubMed  Google Scholar 

  117. Wooster R et al (1995) Identification of the breast cancer susceptibility gene BRCA2. Nature 378(6559):789–792

    Article  CAS  PubMed  Google Scholar 

  118. Tavtigian SV et al (1996) The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat Genet 12(3):333–337

    Article  CAS  PubMed  Google Scholar 

  119. Narod SA, Foulkes WD (2004) BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer 4(9):665–676

    Article  CAS  PubMed  Google Scholar 

  120. Xu X et al (1999) Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation. Nat Genet 22(1):37–43

    Article  CAS  PubMed  Google Scholar 

  121. Brodie SG et al (2001) Multiple genetic changes are associated with mammary tumorigenesis in Brca1 conditional knockout mice. Oncogene 20(51):7514–7523

    Article  CAS  PubMed  Google Scholar 

  122. Lim E et al (2009) Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med 15(8):907–913

    Article  CAS  PubMed  Google Scholar 

  123. Ludwig T et al (2001) Development of mammary adenocarcinomas by tissue-specific knockout of Brca2 in mice. Oncogene 20(30):3937–3948

    Article  CAS  PubMed  Google Scholar 

  124. Cheung AM et al (2004) Brca2 deficiency does not impair mammary epithelium development but promotes mammary adenocarcinoma formation in p53(+/−) mutant mice. Cancer Res 64(6):1959–1965

    Article  CAS  PubMed  Google Scholar 

  125. Slamon DJ et al (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235(4785):177–182

    Article  CAS  PubMed  Google Scholar 

  126. Park JW et al (2008) Unraveling the biologic and clinical complexities of HER2. Clin Breast Cancer 8(5):392–401

    Article  CAS  PubMed  Google Scholar 

  127. Hynes NE, MacDonald G (2009) ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol 21(2):177–184

    Article  CAS  PubMed  Google Scholar 

  128. Lee JW et al (2006) Somatic mutations of ERBB2 kinase domain in gastric, colorectal, and breast carcinomas. Clin Cancer Res 12(1):57–61

    Article  CAS  PubMed  Google Scholar 

  129. Kan Z et al (2010) Diverse somatic mutation patterns and pathway alterations in human cancers. Nature 466(7308):869–873

    Article  CAS  PubMed  Google Scholar 

  130. Santarpia L et al (2012) Mutation profiling identifies numerous rare drug targets and distinct mutation patterns in different clinical subtypes of breast cancers. Breast Cancer Res Treat 134(1):333–343

    Article  CAS  PubMed  Google Scholar 

  131. Bose R et al (2013) Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov 3(2):224–237

    Article  CAS  PubMed  Google Scholar 

  132. Muller WJ et al (1988) Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. Cell 54(1):105–115

    Article  CAS  PubMed  Google Scholar 

  133. Bouchard L et al (1989) Stochastic appearance of mammary tumors in transgenic mice carrying the MMTV/c-neu oncogene. Cell 57(6):931–936

    Google Scholar 

  134. Andrechek ER et al (2000) Amplification of the neu/erbB-2 oncogene in a mouse model of mammary tumorigenesis. Proc Natl Acad Sci USA 97(7):3444–3449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Guy CT et al (1992) Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc Natl Acad Sci USA 89(22):10578–10582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Siegel PM et al (1994) Novel activating mutations in the neu proto-oncogene involved in induction of mammary tumors. Mol Cell Biol 14(11):7068–7077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Siegel PM et al (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(8):2149–2164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Kwong KY, Hung MC (1998) A novel splice variant of HER2 with increased transformation activity. Mol Carcinog 23(2):62–68

    Article  CAS  PubMed  Google Scholar 

  139. Marchini C et al (2011) The human splice variant Delta16HER2 induces rapid tumor onset in a reporter transgenic mouse. PLoS One 6(4):e18727

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Alajati A et al (2013) Mammary tumor formation and metastasis evoked by a HER2 splice variant. Cancer Res 73(17):5320–5327

    Article  CAS  PubMed  Google Scholar 

  141. Wang TC et al (1994) Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice. Nature 369(6482):669–671

    Article  CAS  PubMed  Google Scholar 

  142. Akli S et al (2007) Overexpression of the low molecular weight cyclin E in transgenic mice induces metastatic mammary carcinomas through the disruption of the ARF-p53 pathway. Cancer Res 67(15):7212–7222

    Article  CAS  PubMed  Google Scholar 

  143. Sinn E et al (1987) Coexpression of MMTV/v-Ha-ras and MMTV/c-myc genes in transgenic mice: synergistic action of oncogenes in vivo. Cell 49(4):465–475

    Article  CAS  PubMed  Google Scholar 

  144. Shackleford GM et al (1993) Mouse mammary tumor virus infection accelerates mammary carcinogenesis in Wnt-1 transgenic mice by insertional activation of int-2/Fgf-3 and hst/Fgf-4. Proc Natl Acad Sci USA 90(2):740–744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Campbell IG et al (2004) Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res 64(21):7678–7681

    Article  CAS  PubMed  Google Scholar 

  146. Loi S et al (2010) PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer. Proc Natl Acad Sci USA 107(22):10208–10213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Dunlap J et al (2010) Phosphatidylinositol-3-kinase and AKT1 mutations occur early in breast carcinoma. Breast Cancer Res Treat 120(2):409–418

    Article  CAS  PubMed  Google Scholar 

  148. Koren S, Bentires-Alj M (2013) Mouse models of PIK3CA mutations: one mutation initiates heterogeneous mammary tumors. FEBS J 280(12):2758–2765

    Article  CAS  PubMed  Google Scholar 

  149. Blanpain C (2013) Tracing the cellular origin of cancer. Nat Cell Biol 15(2):126–134

    Article  CAS  PubMed  Google Scholar 

  150. Koren S et al (2015) PIK3CAH1047R induces multipotency and multi-lineage mammary tumors. Nature 525:114–118

    Article  CAS  PubMed  Google Scholar 

  151. Cancer Genome Atlas Network (2012) Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61–70

    Article  CAS  Google Scholar 

  152. Lin EY et al (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(5):2113–2126

    Article  PubMed  PubMed Central  Google Scholar 

  153. Bertheau P et al (2013) p53 in breast cancer subtypes and new insights into response to chemotherapy. Breast 22(Suppl 2):S27–S29

    Article  PubMed  Google Scholar 

  154. Lozano G (2010) Mouse models of p53 functions. Cold Spring Harb Perspect Biol 2(4):a001115

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. Liu G et al (2000) High metastatic potential in mice inheriting a targeted p53 missense mutation. Proc Natl Acad Sci USA 97(8):4174–4179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Olive KP et al (2004) Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. Cell 119(6):847–860

    Article  CAS  PubMed  Google Scholar 

  157. Lang GA et al (2004) Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell 119(6):861–872

    Article  CAS  PubMed  Google Scholar 

  158. Walerych D et al (2012) The rebel angel: mutant p53 as the driving oncogene in breast cancer. Carcinogenesis 33(11):2007–2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Berx G et al (1995) E-cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancers. EMBO J 14(24):6107–6115

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Derksen PW et al (2006) Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis. Cancer Cell 10(5):437–449

    Article  CAS  PubMed  Google Scholar 

  161. Hollander MC, Blumenthal GM, Dennis PA (2011) PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat Rev Cancer 11(4):289–301

    Article  CAS  PubMed  Google Scholar 

  162. Schade B et al (2009) PTEN deficiency in a luminal ErbB-2 mouse model results in dramatic acceleration of mammary tumorigenesis and metastasis. J Biol Chem 284(28):19018–19026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Li Y et al (2001) Deficiency of Pten accelerates mammary oncogenesis in MMTV-Wnt-1 transgenic mice. BMC Mol Biol 2:2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Knobbe CB et al (2008) The roles of PTEN in development, physiology and tumorigenesis in mouse models: a tissue-by-tissue survey. Oncogene 27(41):5398–5415

    Article  CAS  PubMed  Google Scholar 

  165. Li G et al (2002) Conditional loss of PTEN leads to precocious development and neoplasia in the mammary gland. Development 129(17):4159–4170

    CAS  PubMed  Google Scholar 

  166. Huijbers IJ et al (2015) Using the GEMM-ESC strategy to study gene function in mouse models. Nat Protoc 10(11):1755–1785

    Article  CAS  PubMed  Google Scholar 

  167. Doyle A et al (2012) The construction of transgenic and gene knockout/knockin mouse models of human disease. Transgenic Res 21(2):327–349

    Article  CAS  PubMed  Google Scholar 

  168. Platt RJ et al (2014) CRISPR-Cas9 knockin mice for genome editing and cancer modeling. Cell 159(2):440–455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Sanchez-Rivera FJ et al (2014) Rapid modelling of cooperating genetic events in cancer through somatic genome editing. Nature 516(7531):428–431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Cardiff RD et al (2000) The mammary pathology of genetically engineered mice: the consensus report and recommendations from the Annapolis meeting. Oncogene 19(8):968–988

    Article  CAS  PubMed  Google Scholar 

  171. Hollern DP, Andrechek ER (2014) A genomic analysis of mouse models of breast cancer reveals molecular features of mouse models and relationships to human breast cancer. Breast Cancer Res 16(3):R59

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  172. Cardiff RD (2001) Validity of mouse mammary tumour models for human breast cancer: comparative pathology. Microsc Res Tech 52(2):224–230

    Article  CAS  PubMed  Google Scholar 

  173. Cardiff RD (2003) Mouse models of human breast cancer. Comp Med 53(3):250–253

    Google Scholar 

  174. Richmond A, Su Y (2008) Mouse xenograft models vs GEM models for human cancer therapeutics. Dis Model Mech 1(2–3):78–82

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We thank Robert D. Cardiff and Daniel Medina for critical reading of the manuscript.

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Couto, J.P., Bentires-Alj, M. (2017). Mouse Models of Breast Cancer: Deceptions that Reveal the Truth. In: Veronesi, U., Goldhirsch, A., Veronesi, P., Gentilini, O., Leonardi, M. (eds) Breast Cancer. Springer, Cham. https://doi.org/10.1007/978-3-319-48848-6_6

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