Methodological Approaches to Investigate the Effects of Histamine Receptor Targeting Compounds in Preclinical Models of Breast Cancer

  • Diego J. Martinel Lamas
  • Melisa B. Nicoud
  • Helena Sterle
  • Graciela P. Cricco
  • Gabriela A. Martin
  • Graciela A. Cremaschi
  • Hubert G. Schwelberger
  • Elena S. Rivera
  • Vanina A. MedinaEmail author
Part of the Methods in Pharmacology and Toxicology book series (MIPT)


Numerous studies demonstrated the pivotal role of histamine in breast cancer development and progression. This chapter aims to describe different preclinical breast cancer models, including in vitro soft agar clonogenic assay and in vivo chemically induced breast tumors in rats, human triple negative breast cancer (TNBC) xenograft, and murine TNBC syngeneic graft in mice. All these models could be useful and complementary to assess the role of histamine receptor ligands in breast cancer, which could originate advances in novel therapeutics to treat this disease. This chapter also describes the gold standard radiometric techniques to evaluate the activity of histamine metabolizing enzymes in breast cancer specimens.

Key words

Allograft Breast cancer Carcinogenesis Clonogenic assay Proliferation Syngeneic model Tumor growth Xenogeneic model Xenograft 


  1. 1.
    World Health Organization (2011). Global Health Observatory Data Repository Number of deaths (World) by cause. Available from: 31.10.2013
  2. 2.
    Ferlay J, Soerjomataram I, Dikshit R et al (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns. Int J Cancer 136:E359–E386CrossRefPubMedGoogle Scholar
  3. 3.
    Sharma S, Barry M, Gallagher DJ et al (2015) An overview of triple negative breast cancer for surgical oncologists. Surg Oncol 24:276–283CrossRefPubMedGoogle Scholar
  4. 4.
    Medina VA, Rivera ES (2010) Histamine receptors and cancer pharmacology. Br J Pharmacol 161:755–767CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Voskoglou-Nomikos T, Pater JL, Seymour L (2003) Clinical predictive value of the in vitro cell line, human xenograft, and mouse allograft preclinical cancer models. Clin Cancer Res 9:4227–4239PubMedGoogle Scholar
  6. 6.
    Medina VA, Coruzzi G, Martinel Lamas DJ et al (2013) Histamine in cancer. In: Stark H (ed) Histamine H4 receptor: A novel drug target in immunoregulatory and inflammatory diseases. Versita, LondonGoogle Scholar
  7. 7.
    Martinel Lamas DJ, Rivera ES, Medina VA (2015) Histamine H4 receptor: insights into a potential therapeutic target in breast cancer. Front Biosci (Schol Ed) 7:1–9CrossRefGoogle Scholar
  8. 8.
    Davio CA, Cricco GP, Martin G et al (1994) Effect of histamine on growth and differentiation of the rat mammary gland. Agents Actions Spec No:C115–7Google Scholar
  9. 9.
    Maslinski C, KierskaD FW et al (1993) Histamine: its metabolism and localization in mammary gland. Comp Biochem Physiol C 105:269–273CrossRefPubMedGoogle Scholar
  10. 10.
    Wagner W, Ichikawa A, Tanaka S et al (2003) Mouse mammary epithelial histamine system. J Physiol Pharmacol 5:211–223Google Scholar
  11. 11.
    Martinel Lamas DJ, Cortina JE, Ventura C et al (2015) Enhancement of ionizing radiation response by histamine in vitro and in vivo in human breast cancer. Cancer Biol Ther 16:137–148CrossRefPubMedGoogle Scholar
  12. 12.
    Sieja K, Stanosz S, von Mach-Szczypiński J et al (2005) Concentration of histamine in serum and tissues of the primary ductal breast cancer in women. Breast 14:236–241CrossRefPubMedGoogle Scholar
  13. 13.
    von Mach-Szczypiński J, Stanosz S, Sieja K et al (2009) Metabolism of histamine in tissues of primary ductal breast cancer. Metabolism 58:867–870CrossRefGoogle Scholar
  14. 14.
    Cricco G, Davio C, Martín G et al (1994) Histamine as an autocrine growth factor in an experimental mammary carcinoma. Agents Actions 43:17–20CrossRefPubMedGoogle Scholar
  15. 15.
    Davio C, Cricco G, Bergoc R et al (1995) H1 and H2 histamine receptors in experimental carcinomas with an atypical coupling to signal transducers. Biochem Pharmacol 50:91–96CrossRefPubMedGoogle Scholar
  16. 16.
    Rivera E, Davio C, Cricco G et al (1993) Histamine regulation of tumour growth. Role of H1 and H2 receptors. In: Histamine in normal and cancer cell proliferation. Advances in the Bioscience, 89, 299–317. M. García-Caballero, L. Brandes and S. Hosoda. Eds. Pergamon Press, Oxford. ISBN: 0080422020 9780080422022Google Scholar
  17. 17.
    Rivera ES, Cricco GP, Engel NI et al (2000) Histamine as an autocrine growth factor: an unusual role for a widespread mediator. Semin Cancer Biol 10:15–23CrossRefPubMedGoogle Scholar
  18. 18.
    Davio C, Cricco G, Andrade N et al (1993) H1 and H2 histamine receptors in human mammary carcinomas. Agents Actions 38:C172–C174CrossRefGoogle Scholar
  19. 19.
    Lemos B, Davio C, Gass H et al (1995) Histamine receptors in human mammary gland, different benign lesions and mammmary carcinomas. Inflamm Res 44:68–69CrossRefGoogle Scholar
  20. 20.
    Parshad R, Hazrah P, Kumar S et al (2005) Effect of preoperative short course famotidine on TILs and survival in breast cancer. Indian J Cancer 42:185–190PubMedGoogle Scholar
  21. 21.
    Medina V, Cricco G, Nuñez M et al (2006) Histamine-mediated signaling processes in human malignant mammary cells. Cancer Biol Ther 5:1462–1471CrossRefPubMedGoogle Scholar
  22. 22.
    Medina V, Croci M, Crescenti E et al (2008) The role of histamine in human mammary carcinogenesis: H3 and H4 receptors as potential therapeutic targets for breast cancer treatment. Cancer Biol Ther 7:27–35CrossRefGoogle Scholar
  23. 23.
    Medina VA, Brenzoni PG, Martinel Lamas DJ et al (2011) Role of histamine H4 receptor in breast cancer cell proliferation. Front Biosci (Elite Ed) 3:1042–1060Google Scholar
  24. 24.
    Mak IWY, Evaniew N, Ghert M (2014) Lost in translation: animal models and clinical trials in cancer treatment. Am J Transl Res 6:114–118PubMedPubMedCentralGoogle Scholar
  25. 25.
    Fiebig HH, Maier A, Burger AM (2004) Clonogenic assay with established human tumour xenografts: correlation of in vitro to in vivo activity as a basis for anticancer drug discovery. Eur J Cancer 40:802–820CrossRefPubMedGoogle Scholar
  26. 26.
    Russo J, Gusterson BA, Rogers AE et al (1990) Comparative study of human and rat mammary tumorigenesis. Lab Invest 62:244–278PubMedGoogle Scholar
  27. 27.
    Russo J, Russo IH (2000) Atlas and histologic classification of tumors of the rat mammary gland. J Mammary Gland Biol Neoplasia 5(2):187–200CrossRefPubMedGoogle Scholar
  28. 28.
    Hall EJ, Giaccia AJ (2012) Clinical response of normal tissues. In: Hall EJ, Giaccia AJ, Williams, Wilkins (eds) Radiobiology for radiobiologists, 7th edn. Lippincott, PhiladelphiaGoogle Scholar
  29. 29.
    Pavelic PZ, SlocumHK RYM et al (1980) Colony growth in soft agar of human melanoma, sarcoma, and lung carcinoma cells disaggregated by mechanical and enzymatic methods. Cancer Res 40:2160–2164PubMedGoogle Scholar
  30. 30.
    Manni A, Wright C (1983) Assessment of mitogenesis of the hormone-responsive NMU rat mammary tumor grown in culture in soft agar, using 3H-thymidine incorporation into DNA. Breast Cancer Res Treat 3:287–292CrossRefPubMedGoogle Scholar
  31. 31.
    Price JE, Polyzos A, Zhang RD et al (1990) Tumorigenicity and metastasis of human breast carcinoma cell lines in nude mice. Cancer Res 50:717–721PubMedGoogle Scholar
  32. 32.
    Russo J, Russo IH (1996) Experimentally induced mammary tumors in rats. Breast Cancer Res Treat 39:7–20CrossRefPubMedGoogle Scholar
  33. 33.
    Hamaguchi T, Matsuoka Y, Kawaguchi H et al (2004) Terminal endbuds and acini as the respective major targets for chemical and sporadic carcinogenesis in the mammary glands of human c-Ha-rasprotooncogene transgenic rats. Breast Cancer Res Treat 83:43–56CrossRefPubMedGoogle Scholar
  34. 34.
    Perše M, Cerar A, Injac R et al (2009) N-methylnitrosourea induced breast cancer in rat, the histopathology of the resulting tumours and its drawbacks as a model. Pathol Oncol Res 15:115–121CrossRefPubMedGoogle Scholar
  35. 35.
    Saminathan M, Rai RB, Dhama K et al l (2014) Histopathology and immunohistochemical expression of n-methyl-n-nitrosourea (NMU) induced mammary tumours in sprague-dawley rats. Asian J Anim Vet Adv 9:621–640Google Scholar
  36. 36.
    Chan MM, Lu X, Merchant FM et al (2005) Gene expression profiling of NMU-induced rat mammary tumors: cross species comparison with human breast cancer. Carcinogenesis 26:1343–1353CrossRefPubMedGoogle Scholar
  37. 37.
    Gullino PM, Pettigrew HM, Grantham FH (1975) N-nitrosomethylurea as mammary gland carcinogen in rats. J Natl Cancer Inst 54:401–414PubMedGoogle Scholar
  38. 38.
    Thompson HT, Adlakha H (1991) Dose-responsive induction of mammary gland carcinomas by the intraperitoneal injection of 1-methyl-l-nitrosourea. Cancer Res 51:3411–3415PubMedGoogle Scholar
  39. 39.
    Rivera ES, Andrade N, Martin G et al (1994) Induction of mammary tumors in rat by intraperitoneal injection of NMU: histopathology and estral cycle influence. Cancer Lett 86:223–228CrossRefPubMedGoogle Scholar
  40. 40.
    Martin G, Melito G, Rivera E et al (1996) Effect of tamoxifen on intraperitoneal N-nitroso-N-methylurea induced tumors. Cancer Lett 100:227–234CrossRefPubMedGoogle Scholar
  41. 41.
    Martin G, Rivera E, Daivo C et al (1996) Receptors characterization of intraperitoneally N-nitroso-N-methylurea-induced mammary tumors in rats. Cancer Lett 101:1–8CrossRefPubMedGoogle Scholar
  42. 42.
    Martin G, Davio C, Rivera E et al (1997) Hormone dependence of mammary tumors induced in rats by intraperitoneal NMU injection. Cancer Invest 15:8–17CrossRefPubMedGoogle Scholar
  43. 43.
    Sporn MB, Dowsett SA, Mershon J et al (2004) Role of raloxifene in breast cancer prevention in post menopausal women: clinical evidence and potential mechanisms of action. Clin Ther 26:830–840CrossRefPubMedGoogle Scholar
  44. 44.
    Tsubura A, LaiYC MH et al (2011) Animal models of N-Methyl-N-nitrosourea-induced mammary cancer and retinal degeneration with special emphasis on therapeutic trials. In Vivo 25:11–22PubMedGoogle Scholar
  45. 45.
    Kisková T, Jendželovský R, Rentsen E et al (2014) Resveratrol enhances the chemopreventive effect of celecoxib in chemically induced breast cancer in rats. Eur J Cancer Prev 23:506–513CrossRefPubMedGoogle Scholar
  46. 46.
    Yaacob NS, Yankuzo HM, Devaraj S et al (2015) Anti-tumor action, clinical biochemistry profile and phytochemical constituents of a pharmacologically active fraction of S. crispus in NMU-induced rat mammary tumour model. PLoS One. doi: 10.1371/journal.pone.0126426 2015 Google Scholar
  47. 47.
    McCormick DL, Adamowski CB, Fiks A et al (1981) Lifetime dose-response relationships for mammary tumor induction by a single administration of N-methyl-N-nitrosourea. Cancer Res 41:1690–1694PubMedGoogle Scholar
  48. 48.
    Kelland LR (2004) “Of mice and men”: values and liabilities of the athymic nude mouse model in anticancer drug development. Eur J Cancer 40:827–836CrossRefPubMedGoogle Scholar
  49. 49.
    Graham C, Tucker C, Creech J et al (2006) Evaluation of the antitumor efficacy, pharmacokinetics and pharmacodynamics of the histone deacetylase inhibitor depsipeptide in childhood cancer models in vivo. Clin Cancer Res 12:223–234CrossRefPubMedGoogle Scholar
  50. 50.
    Kerbel RS (2003) Human tumor xenografts as predictive preclinical models for anticancer drug activity in humans: better than commonly perceived—but they can be improved. Cancer Biol Ther 2:S134–S139PubMedGoogle Scholar
  51. 51.
    Bibby MC (2004) Orthotopic models of cancer for preclinical drug evaluation: advantages and disadvantages. Eur J Cancer 40:852–857CrossRefPubMedGoogle Scholar
  52. 52.
    Badve S, Dabbs DJ, Schnitt SJ et al (2011) Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists. Mod Pathol 24:157–167CrossRefPubMedGoogle Scholar
  53. 53.
    Pierce JE (1990) Xenograft models in immunodeficient animals. I. Nude mice: spontaneous and experimental metastasis models. In: S.A. Brooks and U. Schumacher© Humana Press Inc (ed) Methods in Molecular Medicine, vol 58: Metastasis Research Protocols, Totowa NJ (ed) Cell Behavior In Vitro and In Vivo Vol. 2. pp 205–213.Google Scholar
  54. 54.
    Davio C, Mladovan A, Lemos B et al (2002) H1 and H2 histamine receptors mediate the production of inositol phosphates but not cAMP in human breast epithelial cells. Inflamm Res 51:1–7CrossRefPubMedGoogle Scholar
  55. 55.
    Martinel Lamas D, Croci M, Carabajal E et al (2013) Therapeutic potencial of histamine H4 receptor agonists in triple-negative human breast cancer experimental model. Br J Pharmacol 170:188–199CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Martinel Lamas DJ, Nicoud MB, Sterle HA et al (2015) Selective cytoprotective effect of histamine on doxorubicin-induced hepatic and cardiac toxicity in animal models. Cell Death Discov 1:15059CrossRefPubMedGoogle Scholar
  57. 57.
    Kmiecik T, Otocka-Kmiecik A, Górska-Ciebiada M et al (2012) T lymphocytes as a target of histamine action. Arch Med Sci 8:154–161CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Dushyanthen S, Beavis PA, Savas P et al (2015) Relevance of tumor-infiltrating lymphocytes in breast cancer. BMC Med 13:202CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Hegyesi L, Colombo E, Pállinger S et al (2007) Impact of systemic histamine deficiency on the crosstalk between mammary adenocarcinoma and T cells. J Pharmacol Sci 105:66–73CrossRefPubMedGoogle Scholar
  60. 60.
    Dexter DL, Kowalski HM, Blazar BA et al (1978) Heterogeneity of tumor cells from a single mouse mammary tumor. Cancer Res 38:3174–3181PubMedGoogle Scholar
  61. 61.
    Pulaski BA, Ostrand-Rosenberg S (1998) Reduction of established spontaneous mammary carcinoma metastases following immunotherapy with major histocompatibility complex class II and B7.1 cell-based tumor vaccines. Cancer Res 58:1486–1493PubMedGoogle Scholar
  62. 62.
    Lelekakis M, Moseley JM, Martin TJ et al (1999) A novel orthotopic model of breast cancer metastasis to bone. Clin Exp Metastasis 17:163–170CrossRefPubMedGoogle Scholar
  63. 63.
    Heppner GH, Miller FR, Shekhar PM (2000) Nontransgenic models of breast cancer. Breast Cancer Res 2:331–334CrossRefPubMedGoogle Scholar
  64. 64.
    DuPre’ SA, Hunter KW Jr (2007) Murine mammary carcinoma 4T1 induces a leukemoid reaction with splenomegaly: association with tumor-derived growth factors. Exp Mol Pathol 82:12–24CrossRefPubMedGoogle Scholar
  65. 65.
    Hegyesi H, Horváth B, Pállinger E et al (2005) Histamine elevates the expression of Ets-1, a protooncogen in human melanoma cell lines through H2 receptor. FEBS Lett 579:2475–2479CrossRefPubMedGoogle Scholar
  66. 66.
    Parsons SJ, Parsons JT (2004) Src family kinases, key regulators of signal transduction. Oncogene 23:7906–7909CrossRefPubMedGoogle Scholar
  67. 67.
    He G, Lin J, Cai W et al (2014) Associations of polymorphisms in histidine decarboxylase, histamine N-methyltransferase and histamine receptor H3 genes with breast cancer. PLoS One 9(5):e97728CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Frick LR, Rapanelli M, Arcos ML et al (2011) Oral administration of fluoxetine alters the proliferation/apoptosis balance of lymphoma cells and up-regulates T cell immunity in tumor-bearing mice. Eur J Pharmacol 659:265–272CrossRefPubMedGoogle Scholar
  69. 69.
    Medina MA, Urdiales JL, Rodriguez-Caso C et al (2003) Biogenic amines and polyamines: similar biochemistry for different physiological missions and biomedical applications. Crit Rev Biochem Mol Biol 38:23–59CrossRefPubMedGoogle Scholar
  70. 70.
    Medina MA, Correa-Fiz F, Rodriguez-Caso C et al (2005) A comprehensive view of polyamine and histamine metabolism to the light of new technologies. J Cell Mol Med 9:854–864CrossRefPubMedGoogle Scholar
  71. 71.
    Levine RJ, Watts DE (1966) A sensitive and specific assay for histidine decarboxylase activity. Biochem Pharmacol 5:841–849CrossRefGoogle Scholar
  72. 72.
    Hakanson R, Larsson LI, Liedberg G et al (1977) Suppression of rat stomach histidine decarboxylase activity by histamine: H2-receptor-mediated feed-back. J Physiol 269:643–667CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Engel N, Cricco G, Davio C et al (1996) Histamine regulates the expression of histidine decarboxylase in NMU-induced tumors in rats. Inflamm Res 45(S1):S64–S65CrossRefPubMedGoogle Scholar
  74. 74.
    Tran VT, Snyder SH (1981) Histidine decarboxylase. Purification from fetal rat liver, immunologic properties, and histochemical localization in brain and stomach. J Biol Chem 256:680–686PubMedGoogle Scholar
  75. 75.
    Kuefner MA, Feurle J, Petersen J et al (2014) Influence of iodinated contrast media on the activities of histamine inactivating enzymes diamine oxidase and histamine N-methyltransferase in vitro. Allergol Immunopathol 42:324–328CrossRefGoogle Scholar
  76. 76.
    Cricco G, Engel N, Crocci M et al (1997) Fluoromethylhistidine inhibits tumor growth without producing depletion of endogenous histamine. Inflamm Res 46:59–60CrossRefPubMedGoogle Scholar
  77. 77.
    Manni A, Wright C (1983) Effect of tamoxifen and alpha-difluoromethylornithine on clones of nitrosomethylurea-induced rat mammary tumor cells grown in soft agar culture. Cancer Res 43:1084–1086PubMedGoogle Scholar
  78. 78.
    Kilkenny C, Browne W, Cuthill IC et al (2010) NC3Rs reporting guidelines working group. animal research: reporting in vivo experiments: the ARRIVE guidelines. Br J Pharmacol 160:1577–1579CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    McGrath JC, Drummond GB, McLachlan EM et al (2010) Guidelines for reporting experiments involving animals: the ARRIVE guidelines. Br J Pharmacol 160:1573–1576CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Warin R, Xiao D, Arlotti JA et al (2010) Inhibition of human breast cancer xenograft growth by cruciferous vegetable constituent benzyl isothiocyanate. Mol Carcinog 49:500–507CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Kokolus KM, Capitano ML, Lee CT et al (2013) Baseline tumor growth and immune control in laboratory mice are significantly influenced by subthermoneutral housing temperature. Proc Natl Acad Sci U S A 110:20176–20181CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Minton K (2014) Tumour-bearing mice feel the cold. Nat Rev Immunol 14:7Google Scholar
  83. 83.
    Spallanzani RG, Dalotto-Moreno T, Raffo Iraolagoitia XL et al (2013) Expansion of CD11b(+)Ly6G (+)Ly6C (int) cells driven by medroxyprogesterone acetate in mice bearing breast tumors restrains NK cell effector functions. Cancer Immunol Immunother 62:1781–1795CrossRefPubMedGoogle Scholar
  84. 84.
    Kramer MG, Masner M, Casales E et al (2015) Neoadjuvant administration of Semliki Forest virus expressing interleukin-12 combined with attenuated Salmonella eradicates breast cancer metastasis and achieves long-term survival in immunocompetent mice. BMC Cancer 15:620CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Nitta Y, Ohshita J, Liu H et al (2010) Expression of recombinant human histidine decarboxylase with full length and C-terminal truncated forms in yeast and bacterial cells. J Biol Macromol 10:73–82Google Scholar
  86. 86.
    Parasuraman S, Raveendran R, Kesavan R (2010) Blood sample collection in small laboratory animals. J Pharmacol Pharmacother 1:87–93CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media LLC 2017

Authors and Affiliations

  • Diego J. Martinel Lamas
    • 1
    • 2
  • Melisa B. Nicoud
    • 2
  • Helena Sterle
    • 3
  • Graciela P. Cricco
    • 1
  • Gabriela A. Martin
    • 1
    • 4
  • Graciela A. Cremaschi
    • 1
    • 3
  • Hubert G. Schwelberger
    • 5
  • Elena S. Rivera
    • 1
  • Vanina A. Medina
    • 1
    • 2
    Email author
  1. 1.Laboratory of Radioisotopes, School of Pharmacy and BiochemistryUniversity of Buenos AiresBuenos AiresArgentina
  2. 2.Laboratory of Tumor Biology and Inflammation, Institute for Biomedical Research (BIOMED), School of Medical SciencesPontifical Catholic University of Argentina (UCA), and the National Scientific and Technical Research Council (CONICET)Buenos AiresArgentina
  3. 3.Neuroimmunomodulation and Molecular Oncology Division, Institute for Biomedical Research (BIOMED), School of Medical SciencesPontifical Catholic University of Argentina (UCA), and the National Scientific and Technical Research Council (CONICET)Buenos AiresArgentina
  4. 4.National Scientific and Technical Research Council (CONICET)Buenos AiresArgentina
  5. 5.Molecular Biology Laboratory, Department of Visceral, Transplant and Thoracic SurgeryMedical University InnsbruckInnsbruckAustria

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