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Mouse models of breast cancer in preclinical research

Abstract

Breast cancer remains the second leading cause of cancer death among woman, worldwide, despite advances in identifying novel targeted therapies and the development of treating strategies. Classification of clinical subtypes (ER+, PR+, HER2+, and TNBC (Triple-negative)) increases the complexity of breast cancers, which thus necessitates further investigation. Mouse models used in breast cancer research provide an essential approach to examine the mechanisms and genetic pathway in cancer progression and metastasis and to develop and evaluate clinical therapeutics. In this review, we summarize tumor transplantation models and genetically engineered mouse models (GEMMs) of breast cancer and their applications in the field of human breast cancer research and anti-cancer drug development. These models may help to improve the knowledge of underlying mechanisms and genetic pathways, as well as creating approaches for modeling clinical tumor subtypes, and developing innovative cancer therapy.

References

  1. 1.

    Kweon SS. Updates on Cancer Epidemiology in Korea, 2018. Chonnam Med J 2018; 54(2): 90–100.

  2. 2.

    Jung KW, Won YJ, Kong HJ, Lee ES; Community of Population-Based Regional Cancer Registries. Cancer Statistics in Korea: Incidence, Mortality, Survival, and Prevalence in 2015. Cancer Res Treat 2018; 50(2): 303–316.

  3. 3.

    Althuis MD, Dozier JM, Anderson WF, Devesa SS, Brinton LA. Global trends in breast cancer incidence and mortality 1973–1997. Int J Epidemiol 2005; 34(2): 405–412.

  4. 4.

    Kim IS, Baek SH. Mouse models for breast cancer metastasis. Biochem Biophys Res Commun 2010; 394(3): 443–447.

  5. 5.

    Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lønning PE, Børresen-Dale AL, Brown PO, Botstein D. Molecular portraits of human breast tumours. Nature 2000; 406(6797): 747–752.

  6. 6.

    Cardiff RD, Kenney N. 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 2011; 3(6).

  7. 7.

    Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Lønning PE, Børresen-Dale AL. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 2001; 98(19): 10869–10874.

  8. 8.

    Osborne CK, Schiff R. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med 2011; 62: 233–247.

  9. 9.

    Palmieri C, Patten DK, Januszewski A, Zucchini G, Howell SJ. Breast cancer: current and future endocrine therapies. Mol Cell Endocrinol 2014; 382(1): 695–723.

  10. 10.

    Luque-Cabal M, García-Teijido P, Fernández-Pérez Y, Sánchez-Lorenzo L, Palacio-Vázquez I. Mechanisms Behind the Resistance to Trastuzumab in HER2-Amplified Breast Cancer and Strategies to Overcome It. Clin Med Insights Oncol 2016; 10(Suppl 1): 21–30.

  11. 11.

    Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortés J; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 2015; 372(8): 724–734.

  12. 12.

    Fan W, Chang J, Fu P. Endocrine therapy resistance in breast cancer: current status, possible mechanisms and overcoming strategies. Future Med Chem 2015; 7(12): 1511–1519.

  13. 13.

    Palomeras S, Ruiz-Martínez S, Puig T. Targeting Breast Cancer Stem Cells to Overcome Treatment Resistance. Molecules 2018; 23(9).

  14. 14.

    Cho SY, Kang W, Han JY, Min S, Kang J, Lee A, Kwon JY, Lee C, Park H. An Integrative Approach to Precision Cancer Medicine Using Patient-Derived Xenografts. Mol Cells Mol Cells Mol Cells 2016; 39(2): 77–86.

  15. 15.

    Rygaard J, Povlsen CO. Heterotransplantation of a human malignant tumour to “Nude” mice. Acta Pathol Microbiol Scand 1969; 77(4): 758–760.

  16. 16.

    Zhang Y, Zhang GL, Sun X, Cao KX, Ma C, Nan N, Yang GW, Yu MW, Wang XM. Establishment of a murine breast tumor model by subcutaneous or orthotopic implantation. Oncol Lett 2018; 15(5): 6233–6240.

  17. 17.

    Ding H, Quan H, Yan W, Han J. Silencing of SOX12 by shRNA suppresses migration, invasion and proliferation of breast cancer cells. Biosci Rep 2016.

  18. 18.

    Xiao X, Chen B, Liu X, Liu P, Zheng G, Ye F, Tang H, Xie X. Diallyl disulfide suppresses SRC/Ras/ERK signaling-mediated proliferation and metastasis in human breast cancer by up-regulating miR-34a. PLoS One 2014; 9(11): e112720.

  19. 19.

    Tang H, Liu P, Yang L, Xie X, Ye F, Wu M, Liu X, Chen B, Zhang L, Xie X. miR-185 suppresses tumor proliferation by directly targeting E2F6 and DNMT1 and indirectly upregulating BRCA1 in triple-negative breast cancer. Mol Cancer Ther 2014; 13(12): 3185–3197.

  20. 20.

    Holliday DL, Speirs V. Choosing the right cell line for breast cancer research. Breast Cancer Res 2011; 13(4): 215.

  21. 21.

    Hoffman RM. Orthotopic metastatic mouse models for anticancer drug discovery and evaluation: a bridge to the clinic. Invest New Drugs 1999; 17(4): 343–359.

  22. 22.

    Borges S, Perez EA, Thompson EA, Radisky DC, Geiger XJ, Storz P. Effective Targeting of Estrogen Receptor-Negative Breast Cancers with the Protein Kinase D Inhibitor CRT0066101. Mol Cancer Ther 2015; 14(6): 1306–1316.

  23. 23.

    Zhang C, Yan Z, Arango ME, Painter CL, Anderes K. Advancing bioluminescence imaging technology for the evaluation of anticancer agents in the MDA-MB-435-HAL-Luc mammary fat pad and subrenal capsule tumor models. Clin Cancer Res 2009; 15(1): 238–246.

  24. 24.

    Aslakson CJ, Miller FR. Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor. Cancer Res 1992; 52(6): 1399–1405.

  25. 25.

    Cochrane DR, Bernales S, Jacobsen BM, Cittelly DM, Howe EN, D’ Amato NC, Spoelstra NS, Edgerton SM, Jean A, Guerrero J, Gómez F, Medicherla S, Alfaro IE, McCullagh E, Jedlicka P, Torkko KC, Thor AD, Elias AD, Protter AA, Richer JK. Role of the androgen receptor in breast cancer and preclinical analysis of enzalutamide. Breast Cancer Res 2014; 16(1): R7.

  26. 26.

    Cerliani JP, Guillardoy T, Giulianelli S, Vaque JP, Gutkind JS, Vanzulli SI, Martins R, Zeitlin E, Lamb CA, Lanari C. Interaction between FGFR-2, STAT5, and progesterone receptors in breast cancer. Cancer Res 2011; 71(10): 3720–3731.

  27. 27.

    Whittle JR, Lewis MT, Lindeman GJ, Visvader JE. Patient-derived xenograft models of breast cancer and their predictive power. Breast Cancer Res 2015; 17: 17.

  28. 28.

    Hoffman RM. Patient-derived orthotopic xenografts: better mimic of metastasis than subcutaneous xenografts. Nat Rev Cancer 2015; 15(8): 451–452.

  29. 29.

    Hidalgo M, Amant F, Biankin AV, Budinská E, Byrne AT, Caldas C, Clarke RB, de Jong S, Jonkers J, Maelandsmo GM, Roman S, Seoane J, Trusolino L, Villanueva A. Patient-derived xenograft models: an emerging platform for translational cancer research. Cancer Discov 2014; 4(9): 998–1013.

  30. 30.

    Gao H, Korn JM, Ferretti S, Monahan JE, Wang Y, Singh M, Zhang C, Schnell C, Yang G, Zhang Y, Balbin OA, Barbe S, Cai H, Casey F, Chatterjee S, Chiang DY, Chuai S, Cogan SM, Collins SD, Dammassa E, Ebel N, Embry M, Green J, Kauffmann A, Kowal C, Leary RJ, Lehar J, Liang Y, Loo A, Lorenzana E, Robert McDonald E 3rd, McLaughlin ME, Merkin J, Meyer R, Naylor TL, Patawaran M, Reddy A, Röelli C, Ruddy DA, Salangsang F, Santacroce F, Singh AP, Tang Y, Tinetto W, Tobler S, Velazquez R, Venkatesan K, Von Arx F, Wang HQ, Wang Z, Wiesmann M, Wyss D, Xu F, Bitter H, Atadja P, Lees E, Hofmann F, Li E, Keen N, Cozens R, Jensen MR, Pryer NK, Williams JA, Sellers WR. High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response. Nat Med 2015; 21(11): 1318–1325.

  31. 31.

    Kopetz S, Lemos R, Powis G. The promise of patient-derived xenografts: the best laid plans of mice and men. Clin Cancer Res 2012; 18(19): 5160–5162.

  32. 32.

    Rosfjord E, Lucas J, Li G, Gerber HP. Advances in patient-derived tumor xenografts: from target identification to predicting clinical response rates in oncology. Biochem Pharmacol 2014; 91(2): 135–143.

  33. 33.

    Pillai SG, Li S, Siddappa CM, Ellis MJ, Watson MA, Aft R. Identifying biomarkers of breast cancer micrometastatic disease in bone marrow using a patient-derived xenograft mouse model. Breast Cancer Res 2018; 20(1): 2.

  34. 34.

    Garrido-Laguna I, Uson M, Rajeshkumar NV, Tan AC, de Oliveira E, Karikari C, Villaroel MC, Salomon A, Taylor G, Sharma R, Hruban RH, Maitra A, Laheru D, Rubio-Viqueira B, Jimeno A, Hidalgo M. Tumor engraftment in nude mice and enrichment in stroma- related gene pathways predict poor survival and resistance to gemcitabine in patients with pancreatic cancer. Clin Cancer Res 2011; 17(17): 5793–5800.

  35. 35.

    Rashid OM, Takabe K. Animal models for exploring the pharmacokinetics of breast cancer therapies. Expert Opin Drug Metab Toxicol 2015; 11(2): 221–230.

  36. 36.

    Singh M, Ramos I, Asafu- Adjei D, Quispe-Tintaya W, Chandra D, Jahangir A, Zang X, Aggarwal BB, Gravekamp C. Curcumin improves the therapeutic efficacy of Listeria(at)-Mage-b vaccine in correlation with improved T-cell responses in blood of a triple-negative breast cancer model 4T1. Cancer Med 2013; 2(4): 571–582.

  37. 37.

    Takahashi K, Nagai N, Ogura K, Tsuneyama K, Saiki I, Irimura T, Hayakawa Y. Mammary tissue microenvironment determines T cell-dependent breast cancer-associated inflammation. Cancer Sci 2015; 106(7): 867–874.

  38. 38.

    Tao K, Fang M, Alroy J, Sahagian GG. Imagable 4T1 model for the study of late stage breast cancer. BMC Cancer 2008; 8: 228.

  39. 39.

    Zhou H, Roy S, Cochran E, Zouaoui R, Chu CL, Duffner J, Zhao G, Smith S, Galcheva- Gargova Z, Karlgren J, Dussault N, Kwan RY, Moy E, Barnes M, Long A, Honan C, Qi YW, Shriver Z, Ganguly T, Schultes B, Venkataraman G, Kishimoto TK. M402, a novel heparan sulfate mimetic, targets multiple pathways implicated in tumor progression and metastasis. PLoS One 2011; 6(6): e21106.

  40. 40.

    Hanahan D, Wagner EF, Palmiter RD. The origins of oncomice: a history of the first transgenic mice genetically engineered to develop cancer. Genes Dev 2007; 21(18): 2258–2270.

  41. 41.

    Cardiff RD, Anver MR, Gusterson BA, Hennighausen L, Jensen RA, Merino MJ, Rehm S, Russo J, Tavassoli FA, Wakefield LM, Ward JM, Green JE. The mammary pathology of genetically engineered mice: the consensus report and recommendations from the Annapolis meeting. Oncogene 2000; 19(8): 968–988.

  42. 42.

    Taneja P, Frazier DP, Kendig RD, Maglic D, Sugiyama T, Kai F, Taneja NK, Inoue K. MMTV mouse models and the diagnostic values of MMTV-like sequences in human breast cancer. Expert Rev Mol Diagn 2009; 9(5): 423–440.

  43. 43.

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

  44. 44.

    Park JW, Neve RM, Szollosi J, Benz CC. Unraveling the biologic and clinical complexities of HER2. Clin Breast Cancer 2008; 8(5): 392–401.

  45. 45.

    Allred DC, Clark GM, Molina R, Tandon AK, Schnitt SJ, Gilchrist KW, Osborne CK, Tormey DC, McGuire WL. Overexpression of HER-2/neu and its relationship with other prognostic factors change during the progression of in situ to invasive breast cancer. Hum Pathol 1992; 23(9): 974–979.

  46. 46.

    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): 954–961.

  47. 47.

    Guy CT, Cardiff RD, Muller WJ. Activated neu induces rapid tumor progression. J Biol Chem 1996; 271(13): 7673–7678.

  48. 48.

    Hwang TS, Han HS, Hong YC, Lee HJ, Paik NS. Prognostic value of combined analysis of cyclin D1 and estrogen receptor status in breast cancer patients. Pathol Int 2003; 53(2): 74–80.

  49. 49.

    Sutherland RL, Musgrove EA. Cyclins and breast cancer. J Mammary Gland Biol Neoplasia 2004; 9(1): 95–104.

  50. 50.

    Maroulakou IG, Anver M, Garrett L, Green JE. Prostate and mammary adenocarcinoma in transgenic mice carrying a rat C3(1) simian virus 40 large tumor antigen fusion gene. Proc Natl Acad Sci USA 1994; 91(23): 11236–11240.

  51. 51.

    Herschkowitz JI, Simin K, Weigman VJ, Mikaelian I, Usary J, Hu Z, Rasmussen KE, Jones LP, Assefnia S, Chandrasekharan S, Backlund MG, Yin Y, Khramtsov AI, Bastein R, Quackenbush J, Glazer RI, Brown PH, Green JE, Kopelovich L, Furth PA, Palazzo JP, Olopade OI, Bernard PS, Churchill GA, Van Dyke T, Perou CM. Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol 2007; 8(5): R76.

  52. 52.

    Oztürk-Winder F, Renner M, Klein D, Müller M, Salmons B, Günzburg WH. The murine whey acidic protein promoter directs expression to human mammary tumors after retroviral transduction. Cancer Gene Ther 2002; 9(5): 421–431.

  53. 53.

    Nielsen LL, Discafani CM, Gurnani M, Tyler RD. Histopathology of salivary and mammary gland tumors in transgenic mice expressing a human Ha-ras oncogene. Cancer Res 1991; 51(14): 3762–3767.

  54. 54.

    Liby K, Neltner B, Mohamet L, Menchen L, Ben- Jonathan N. Prolactin overexpression by MDA-MB-435 human breast cancer cells accelerates tumor growth. Breast Cancer Res Treat 2003; 79(2): 241–252.

  55. 55.

    Jensen MR, Schoepfer J, Radimerski T, Massey A, Guy CT, Brueggen J, Quadt C, Buckler A, Cozens R, Drysdale MJ, Garcia-Echeverria C, Chène P. NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models. Breast Cancer Res 2008; 10(2): R33.

  56. 56.

    Zhang T, Chen Y, Li J, Yang F, Wu H, Dai F, Hu M, Lu X, Peng Y, Liu M, Zhao Y, Yi Z. Antitumor action of a novel histone deacetylase inhibitor, YF479, in breast cancer. Neoplasia 2014; 16(8): 665–677.

  57. 57.

    Kuperwasser C, Dessain S, Bierbaum BE, Garnet D, Sperandio K, Gauvin GP, Naber SP, Weinberg RA, Rosenblatt M. A mouse model of human breast cancer metastasis to human bone. Cancer Res 2005; 65(14): 6130–6138.

  58. 58.

    Marangoni E, Vincent-Salomon A, Auger N, Degeorges A, Assayag F, de Cremoux P, de Plater L, Guyader C, De Pinieux G, Judde JG, Rebucci M, Tran-Perennou C, Sastre-Garau X, Sigal-Zafrani B, Delattre O, Diéras V, Poupon MF. A new model of patient tumor-derived breast cancer xenografts for preclinical assays. Clin Cancer Res 2007; 13(13): 3989–3998.

  59. 59.

    DeRose YS, Wang G, Lin YC, Bernard PS, Buys SS, Ebbert MT, Factor R, Matsen C, Milash BA, Nelson E, Neumayer L, Randall RL, Stijleman IJ, Welm BE, Welm AL. Tumor grafts derived from women with breast cancer authentically reflect tumor pathology, growth, metastasis and disease outcomes. Nat Med 2011; 17(11): 1514–1520.

  60. 60.

    Zhang X, Claerhout S, Prat A, Dobrolecki LE, Petrovic I, Lai Q, Landis MD, Wiechmann L, Schiff R, Giuliano M, Wong H, Fuqua SW, Contreras A, Gutierrez C, Huang J, Mao S, Pavlick AC, Froehlich AM, Wu MF, Tsimelzon A, Hilsenbeck SG, Chen ES, Zuloaga P, Shaw CA, Rimawi MF, Perou CM, Mills GB, Chang JC, Lewis MT. A renewable tissue resource of phenotypically stable, biologically and ethnically diverse, patient-derived human breast cancer xenograft models. Cancer Res 2013; 73(15): 4885–4897.

  61. 61.

    Charafe-Jauffret E, Ginestier C, Bertucci F, Cabaud O, Wicinski J, Finetti P, Josselin E, Adelaide J, Nguyen TT, Monville F, Jacquemier J, Thomassin-Piana J, Pinna G, Jalaguier A, Lambaudie E, Houvenaeghel G, Xerri L, Harel-Bellan A, Chaffanet M, Viens P, Birnbaum D. ALDH1-positive cancer stem cells predict engraftment of primary breast tumors and are governed by a common stem cell program. Cancer Res 2013; 73(24): 7290–7300.

  62. 62.

    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): 105–115.

  63. 63.

    Almholt K, Lund LR, Rygaard J, Nielsen BS, Danø K, Rømer J, Johnsen M. Reduced metastasis of transgenic mammary cancer in urokinase-deficient mice. Int J Cancer 2005; 113(4): 525–532.

  64. 64.

    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): 669–671.

  65. 65.

    Stewart TA, Pattengale PK, Leder P. Spontaneous mammary adenocarcinomas in transgenic mice that carry and express MTV/myc fusion genes. Cell 1984; 38(3): 627–637.

  66. 66.

    Li Y, Hively WP, Varmus HE. Use of MMTV-Wnt-1 transgenic mice for studying the genetic basis of breast cancer. Oncogene 2000; 19(8): 1002–1009.

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Correspondence to Ho Lee.

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Park, M.K., Lee, C.H. & Lee, H. Mouse models of breast cancer in preclinical research. Lab Anim Res 34, 160–165 (2018). https://doi.org/10.5625/lar.2018.34.4.160

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Keywords

  • Breast cancer
  • tumor transplantation model
  • genetically engineered mouse models