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N-Methyl-N-nitrosourea as a mammary carcinogenic agent

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Tumor Biology

Abstract

The administration of chemical carcinogens is one of the most commonly used methods to induce tumors in several organs in laboratory animals in order to study oncologic diseases of humans. The carcinogen agent N-methyl-N-nitrosourea (MNU) is the oldest member of the nitroso compounds that has the ability to alkylate DNA. MNU is classified as a complete, potent, and direct alkylating compound. Depending on the animals' species and strain, dose, route, and age at the administration, MNU may induce tumors' development in several organs. The aim of this manuscript was to review MNU as a carcinogenic agent, taking into account that this carcinogen agent has been frequently used in experimental protocols to study the carcinogenesis in several tissues, namely breast, ovary, uterus, prostate, liver, spleen, kidney, stomach, small intestine, colon, hematopoietic system, lung, skin, retina, and urinary bladder. In this paper, we also reviewed the experimental conditions to the chemical induction of tumors in different organs with this carcinogen agent, with a special emphasis in the mammary carcinogenesis.

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References

  1. Fujiki H. Gist of Dr. Katsusaburo Yamagiwa's papers entitled "Experimental study on the pathogenesis of epithelial tumors" (I to VI reports). Cancer Sci. 2013;105:143–9.

    Article  CAS  Google Scholar 

  2. Jonkers J, Berns A. Animal models of cancer. In: Knowles M, Selby P, editors. Introduction to the cellular and molecular biology of cancer. Great Britain: Oxford University Press; 2005. p. 317–36.

    Google Scholar 

  3. Lijinski W. Carcinogenicity and mutagenicity of N-nitroso compounds. Mol Toxicol. 1987;1:107–19.

    Google Scholar 

  4. Steele V, Lubet R, Moon R. Preclinical animal models for the development of cancer chemoprevention drugs. In: Kelloff G, Hawk E, Sigman C, editors. Cancer chemoprevention, vol. 2. New Jersey: Humana Press; 2004.

    Google Scholar 

  5. Aucher M. Hazards of nitrate, nitrite and N-nitrosocompounds in human nutrition. In: Hathcock J, editor. Nutritional toxicology. New York: Academic; 1982. p. 328–67.

    Google Scholar 

  6. Saffhill R, Margison GP, Oconnor PJ. Mechanisms of carcinogenesis induced by alkylating agents. Biochim Biophys Acta. 1985;823:111–45.

    CAS  PubMed  Google Scholar 

  7. Lijinsky W. N-Nitroso compounds in the diet. Mutat Res Genet Toxicol Environ Mutagen. 1999;443:129–38.

    Article  CAS  Google Scholar 

  8. International Agency for Research on Cancer: Evaluation of the carcinogenic risk of chemicals to humans: some N-nitroso compounds. 17 ed. Lyon; 1978.

  9. Raj A, Mayberry JF, Podas T. Occupation and gastric cancer. Postgrad Med J. 2003;79:252–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Rappe C, Buser HR. Occupational exposure to polychlorinated dioxins and dibenzofurans. Abstr Pap Am Chem Soc. 1980;180:21-CHAS.

    Google Scholar 

  11. Stuff JE, Goh ET, Barrera SL, Bondy ML, Forman MR. Construction of an N-nitroso database for assessing dietary intake. J Food Compos Anal. 2009;22:S42–7.

    Article  CAS  Google Scholar 

  12. Tricker AR. N-nitroso compounds and man: sources of exposure, endogenous formation and occurrence in body fluids. Eur J Cancer Prev. 1997;6:226–68.

    Article  CAS  PubMed  Google Scholar 

  13. Wynder E, Hoffman D. Biological testes for tumorigenic and cilia-toxic activity. In: Wynder E, Hoffman D, editors. Tobacco and tobacco smoke: studies in experimental carcinogenesis. New York: Academic; 1967. p. 179.

    Google Scholar 

  14. Reed PI. N-nitroso compounds, their relevance to human cancer and further prospects for prevention. Eur J Cancer Prev. 1996;5:137–47.

    Article  PubMed  Google Scholar 

  15. Kyrtopoulos SA. DNA adducts in humans after exposure to methylating agents. Mutat Res Fundam Mol Mech. 1998;405:135–43.

    Article  CAS  Google Scholar 

  16. Lijinski W. Interaction with nucleic acids of carcinogenic and mutagenic N-nitroso compounds. In: Cohn W, editor. Progress in nucleic acid research and molecular biology, vol. 17. USA: Academic; 1981. p. 247–70.

    Google Scholar 

  17. Deshpande S. Principles of toxicology. Handbook of food toxicology. New York: Marcel Dekker; 2002. p. 11–40.

    Book  Google Scholar 

  18. Montgomery JA. The design of chemotherapeutic agents. Acc Chem Res. 1986;19:293–300.

    Article  CAS  Google Scholar 

  19. 19 National Center for Biotechnology Information: PubChem Substance Database; CID=12699, Source=Scripps Research Institute Molecular Screening Center. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=12699&loc=ec_rcs. Accessed 30 Jan 2014.

  20. Prentiss A. Vesicant agents. Chemicals in welfare: a treatise on chemical warfare. New York: McGraw-Hill; 1937. p. 177–300.

    Google Scholar 

  21. Reutter S. Hazards of chemical weapons release during war: new perspectives. Environ Health Perspect. 1999;107:985–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Alexander S. Medical report of the Bari Harbor mustard casualties. Mil Surg. 1947;101:1–17.

    CAS  PubMed  Google Scholar 

  23. United Nations Security Council: Report of the mission dispatched by the Secretary General to investigate allegations of the use of chemical weapons in the conflict between the Islamic Republic of Iran and Iraq. New York, USA, United Nations; 1988.

  24. Margison G, O'Connor P. Nucleic acid modification by N-nitroso compounds. In: Grover P, editor. Chemical carcinogens and DNA. Florida: CRC Press; 1979. p. 111–59.

    Google Scholar 

  25. Magee P, Montesano R, Preussman R. N-Nitroso compounds and related carcinogenesis. Washington: ACS Press; 1976.

    Google Scholar 

  26. Singer B, Kusmierek JT. Chemical mutagenesis. Annu Rev Biochem. 1982;51:655–93.

    Article  CAS  PubMed  Google Scholar 

  27. Beranek DT. Distribution of methyl and ethyl adducts following alkylation with monofunctional alkylating agents. Mutat Res. 1990;231:11–30.

    Article  CAS  PubMed  Google Scholar 

  28. Ellison KS, Dogliotti E, Connors TD, Basu AK, Essigmann JM. Site-specific mutagenesis by O-6-alkylguanines located in the chromosomes of mammalian-cells—influence of the mammalian O-6-alkylguanine-DNA alkyltransferase. Proc Natl Acad Sci U S A. 1989;86:8620–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Loveless A. Possible relevance of O-6 alkylation of deoxyguanosine to mutagenicity and carcinogenicity of nitrosamines and nitrosamides. Nature. 1969;223:206–7.

    Article  CAS  PubMed  Google Scholar 

  30. Stephanou G, Vlastos D, Vlachodimitropoulos D, Demopoulos NA. A comparative study on the effect of MNU on human lymphocyte cultures in vitro evaluated by O-6-mdG formation, micronuclei and sister chromatid exchanges induction. Cancer Lett. 1996;109:109–14.

    Article  CAS  PubMed  Google Scholar 

  31. Wurdeman RL, Church KM, Gold B. DNA methylation by N-methyl-N-nitrosourea, N-methyl-N'-nitro-N-nitrosoguanidine, N-nitroso(1-acetoxyethyl)methylamine, and diazomethane—mechanism for the formation of N7-methylguanine in sequence-characterized 5'-P-32-end-Labeled DNA. J Am Chem Soc. 1989;111:6408–12.

    Article  CAS  Google Scholar 

  32. Prager B, Jacobson P, Schmidt P, Stern D. Beilsteins Handbuch der Organischen Chemie. 4th ed. Berlin: Springer; 1922.

    Google Scholar 

  33. von Brüning G. Ueber das Methylhydrazin. Liebigs Ann Chem 889;253:5–14.

  34. Rapoport IA. 85-percent of mutations in sex chromosome under influence of nitrosoethylurea. Dokl Akad Nauk SSSR. 1962;146:1418–21.

    CAS  Google Scholar 

  35. Kolaric K. Combination chemotherapy with 1-methyl-1-nitrosourea (MNU) and cyclophosphamide in solid tumors. Z Krebsforsch Klin Onkol. 1977;89:311–9.

    Article  CAS  Google Scholar 

  36. Sendowski K, Rajewsky MF. DNA-sequence dependence of guanine-O6 alkylation by the N-nitroso carcinogens N-methyl-N-nitrosourea and N-ethyl-N-nitrosourea. Mutat Res. 1991;250:153–60.

    Article  CAS  PubMed  Google Scholar 

  37. Bosland M. Chemical and hormonal induction of prostate cancer in animal models. Urol Oncol. 1996;2:103–10.

    Article  CAS  PubMed  Google Scholar 

  38. Tsubura A, Lai YC, Miki H, Sasaki T, Uehara N, Yuri T, et al. Animal models of N-methyl-N-nitrosourea-induced mammary cancer and retinal degeneration with special emphasis on therapeutic trials. In Vivo. 2011;25:11–22.

    CAS  PubMed  Google Scholar 

  39. O'Connor P, Saffhil R, Margison G. N-Nitrosocompounds: biochemical mechanisms of action. In: Emmelot P, Kriek E, editors. Environmental carcinogens, occurrence, risk: evaluation and mechanisms. Amsterdam: Elsevier/North Holland Press; 1979. p. 73–96.

    Google Scholar 

  40. Yano K, Isobe M. Mutagenicity of N-methyl-N'-aryl-N-nitrosoureas and N-methyl-N'-aryl-N'-methyl-N-nitrosoureas in relation to their alkylating activity. Cancer Res. 1979;39:5147–9.

    CAS  PubMed  Google Scholar 

  41. Brundrett RB, Colvin M, White EH, Mckee J, Hartman PE, Brown DL. Comparison of mutagenicity, anti-tumor activity, and chemical properties of selected nitrosoureas and nitrosoamides. Cancer Res. 1979;39:1328–33.

    CAS  PubMed  Google Scholar 

  42. Reis LO, Favaro WJ, Ferreira U, Billis A, Fazuoli MG, Cagnon VHA. Evolution on experimental animal model for upper urothelium carcinogenesis. World J Urol. 2010;28:499–505.

    Article  CAS  PubMed  Google Scholar 

  43. Cui LB, Yuan S, Dai GD, Pan HX, Chen JF, Song L, et al. Modification of N-methyl-N-nitrosourea initiated bladder carcinogenesis in Wistar rats by terephthalic acid. Toxicol Appl Pharmacol. 2006;210:24–31.

    Article  CAS  PubMed  Google Scholar 

  44. Lijinsky W. Species-differences in nitrosamine carcinogenesis. J Cancer Res Clin Oncol. 1984;108:46–55.

    Article  CAS  PubMed  Google Scholar 

  45. Wijnhoven SWP, van Steeg H. Transgenic and knockout mice for DNA repair functions in carcinogenesis and mutagenesis. Toxicology. 2003;193:171–87.

    Article  CAS  PubMed  Google Scholar 

  46. Naghipur A, Ikonomou MG, Kebarle P, Lown JW. Mechanism of action of (2-haloethyl)nitrosoureas on DNA—discrimination between alternative pathways of DNA-base modification by 1,3-bis(2-fluoroethyl)-1-nitrosourea by using specific deuterium labeling and identification of reaction-products by HPLC tandem mass-spectrometry. J Am Chem Soc. 1990;112:3178–87.

    Article  CAS  Google Scholar 

  47. Lunn G, Sansone E. Dealing with spills of hazardous chemicals: some nitrosamides. Food Chem Toxicol. 1988;26:481–4.

    Article  CAS  PubMed  Google Scholar 

  48. Lunn G, Sansone E, Andrews A, Keefer L. Decontamination and disposal of nitrosoureas and related N-nitroso compounds. Cancer Res. 1988;48:522–6.

    CAS  PubMed  Google Scholar 

  49. Lukasova E, Palecek E, Kruglyakova KE, Zhizhina GP, Smotryaeva MA. Properties of DNA modified with N-methyl-N-nitrosourea. Radiat Environ Biophys. 1977;14:231–8.

    Article  CAS  PubMed  Google Scholar 

  50. Druckrey H, Schmahl D, Muller M, Preussmann R. Erzeugung Von Magenkrebs Durch Nitrosamide An Ratten. Naturwissenschaften. 1961;48:165.

    Article  CAS  Google Scholar 

  51. Janisch W, Schreiber D, Warzok R, Scholtze P. Experiments on rhesus-monkeys (Macaca mulatta) with carcinogens methylnitrosourea and ethylnitrosourea. Arch Geschwulstforsch. 1977;47:123–6.

    CAS  PubMed  Google Scholar 

  52. Adamson RH, Krolikowski FJ, Correa P, Sieber SM, Dalgard DW. Carcinogenicity of 1-methyl-1-nitrosourea in nonhuman primates. J Natl Cancer Inst. 1977;59:415–22.

    Article  Google Scholar 

  53. Stavrou D, Dahme E, Kalich J. Induction of tumors of stomach in mini pigs by methylnitrosourea administration. Res Exp Med. 1976;169:33–43.

    Article  CAS  Google Scholar 

  54. Warzok R, Schneide J, Schreibe D, Janisch W. Experimental brain tumours in dogs. Experientia. 1970;26:303–4.

    Article  CAS  PubMed  Google Scholar 

  55. Corpet DE, Pierre F. How good are rodent models of carcinogenesis in predicting efficacy in humans? A systematic review and meta-analysis of colon chemoprevention in rats, mice and men. Eur J Cancer. 2005;41:1911–22.

    Article  CAS  PubMed  Google Scholar 

  56. Gescher AJ, Steward WP. Relationship between mechanisms, bioavailibility, and preclinical chemopreventive efficacy of resveratrol: a conundrum. Cancer Epidemiol Biomark. 2003;12:953–7.

    CAS  Google Scholar 

  57. Okajima E, Hiramatsu T, Hirao K, Ijuin M, Hirao Y, Babaya K, et al. Urinary-bladder tumors induced by N-butyl-N-(4-hydroxybutyl) nitrosamine in dogs. Cancer Res. 1981;41:1958–66.

    CAS  PubMed  Google Scholar 

  58. Oliveira P, Colaço A, De la Cruz P, Lopes C. Experimental bladder carcinogenesis—rodent models. Exp Oncol. 2006;28:2–11.

    CAS  PubMed  Google Scholar 

  59. Son WC, Gopinath C. Early occurrence of spontaneous tumors in CD-1 mice and Sprague-Dawley rats. Toxicol Pathol. 2004;32:371–4.

    Article  CAS  PubMed  Google Scholar 

  60. Isaacs JT. Genetic control of resistance to chemically-induced mammary adenocarcinogenesis in the rat. Cancer Res. 1986;46:3958–63.

    CAS  PubMed  Google Scholar 

  61. Kumar DG, Parvathi V, Meenakshi P, Rathi MA, Gopalakrishnan VK. Anticancer activity of the ethanolic extract of Crateva nurvala bark against testosterone and MNU-induced prostate cancer in rats. Chin J Nat Med. 2012;10:334–8.

    Google Scholar 

  62. Reddy BS, Watanabe K, Weisburger JH. Effect of high-fat diet on colon carcinogenesis in F344 rats treated with 1,2-dimethylhydrazine, methylazoxymethanol acetate, or methylnitrosourea. Cancer Res. 1977;37:4156–9.

    CAS  PubMed  Google Scholar 

  63. Takahashi H, Uemura Y, Nakao I, Tsubura A. Induction of mammary carcinomas by the direct application of crystalline N-methyl-N-nitrosourea onto rat mammary gland. Cancer Lett. 1995;92:105–11.

    Article  CAS  PubMed  Google Scholar 

  64. Raghavan D, Debruyne F, Herr H, Jocham D, Kakizoe T, Okajima E, et al. Developments in bladder cancer. In: Allen R, editor. Experimental models of bladder cancer: a critical review. New York: Liss; 1986. p. 171–208.

    Google Scholar 

  65. Knox P. Carcinogenic nitrosamides and cell cultures. Nature. 1976;671–73.

  66. Esendagli G, Yilmaz G, Canpinar H, Gunel-Ozcan A, Guc M, Guc D. Coexistence of different tissue tumourigenesis in an N-methyl-N-nitrosourea-induced mammary carcinoma model: a histopathological report in Sprague-Dawley rats. Lab Anim. 2009;43(1):60–4.

  67. Miyazono Y, Harada K, Sugiyama K, Ueno M, Torii M, Kato I, et al. Toxicological characterization of N-methyl-N-nitrosourea-induced cataract in rats by LC/MS-based metabolomic analysis. J Appl Toxicol. 2011;31:655–62.

    Article  CAS  PubMed  Google Scholar 

  68. Kiuchi K, Yoshizawa K, Moriguchi K, Tsubura A. Rapid induction of cataract by a single intraperitoneal administration of N-methyl-N-nitrosourea in 15-day-old Sprague-Dawley (Jcl: SD) rats. Exp Toxicol Pathol. 2002;54:181–6.

    Article  PubMed  Google Scholar 

  69. Yoshizawa K, Oishi Y, Nambu H, Yamamoto D, Yang JH, Senzaki H, et al. Cataractogenesis in neonatal Sprague-Dawley rats by N-methyl-N-nitrosourea. Toxicol Pathol. 2000;28:555–64.

    Article  CAS  PubMed  Google Scholar 

  70. Roy B, Fujimoto N, Watanabe H, Ito A. Induction of cataract in methylnitrosourea treated Fisher (F344) rats. Hiroshima J Med Sci. 1989;38:95–8.

    CAS  PubMed  Google Scholar 

  71. Steele VE, Moon RC, Lubet RA, Grubbs CJ, Reddy BS, Wargovich M, et al. Preclinical efficacy evaluation of potential chemopreventive agents in animal carcinogenesis models—methods and results from the NCI chemoprevention drug development program. J Cell Biochem. 1994;20:32–54.

    Article  CAS  Google Scholar 

  72. Gal A, Baba A, Miclaus V, Bouari C, Taulescu M, Bolfã P, et al. Comparative aspects regarding MNU-induced mammary carcinogenesis in immature Sprague-Dawley and Wistar rats. Bull UASVM Vet Med. 2011;68:159–63.

    Google Scholar 

  73. Gullino PM, Pettigrew HM, Grantham FH. N-nitrosomethylurea as mammary gland carcinogen in rats. J Natl Cancer Inst. 1975;54:401–14.

    CAS  PubMed  Google Scholar 

  74. International Agency for Research on Cancer: Hormonal contraception and post-menopausal hormonal therapy. 1999;361–30.

  75. Pazos P, Lanari C, Meissm R, Charreau E, Pasqualini C. Mammary carcinogenesis induced by N-methyl-N-nitrosourea (MNU) and medroxyprogesterone acetate (MPA) in BALB/c mice. Breast Cancer Res Treat. 1991;20:133–8.

    Article  CAS  Google Scholar 

  76. Faustino-Rocha A, Oliveira PA, Pinho-Oliveira J, Teixeira-Guedes C, Soares-Maia R, da Costa RG, et al. Estimation of rat mammary tumor volume using caliper and ultrasonography measurements. Lab Anim. 2013;42:217–24.

    Article  Google Scholar 

  77. Russo J, Russo IH. Atlas and histologic classification of tumors of the rat mammary gland. J Mammary Gland Biol Neoplasia. 2000;5:187–200.

    Article  CAS  PubMed  Google Scholar 

  78. Russo J, Gusterson BA, Rogers AE, Russo IH, Wellings SR, Vanzwieten MJ. Biology of disease—comparative study of human and rat mammary tumorigenesis. Lab Investig. 1990;62:244–78.

    CAS  PubMed  Google Scholar 

  79. Shafiee R, Javanbakht J, Atyabi N, Kheradmand P, Kheradmand D, Bahrami A, Daraei H, Khadivar F. Diagnosis, classification and grading of canine mammary tumours as a model to study human breast cancer: an Clinico-Cytohistopathological study with environmental factors influencing public health and medicine. Cancer Cell Int. 2013;13.

  80. Deboer MD. Animal models of anorexia and cachexia. Expert Opin Drug Discov. 2009;4:1145–55.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Bennani-Baiti N, Walsh D. Animal models of the cancer anorexia-cachexia syndrome. Support Care Cancer. 2011;19:1451–63.

    Article  PubMed  Google Scholar 

  82. Tisdale MJ. Cancer cachexia. Curr Opin Gastroenterol. 2010;26:146–51.

    Article  PubMed  Google Scholar 

  83. Tisdale MJ. Biology of cachexia. J Natl Cancer Inst. 1997;89:1763–73.

    Article  CAS  PubMed  Google Scholar 

  84. Morley JE, Thomas DR, Wilson MMG. Cachexia: pathophysiology and clinical relevance. Am J Clin Nutr. 2006;83:735–43.

    CAS  PubMed  Google Scholar 

  85. Dewys WD, Begg C, Lavin PT, Band PR, Bennett JM, Bertino JR, et al. Prognostic effect of weight loss prior to chemotherapy in cancer patients. Am J Med. 1980;69:491–7.

    Article  CAS  PubMed  Google Scholar 

  86. Tan BHL, Fearon KCH. Cachexia: prevalence and impact in medicine. Curr Opin Clin Nutr Metab Care. 2008;11:400–7.

    Article  PubMed  Google Scholar 

  87. MacDonald N, Easson AM, Mazurak VC, Dunn GP, Baracos VE. Understanding and managing cancer cachexia. J Am Coll Surg. 2003;197:143–61.

    Article  PubMed  Google Scholar 

  88. Stewart GD, Skipworth RJE, Fearon KCH. Cancer cachexia and fatigue. Clin Med. 2006;6:140–3.

    Article  Google Scholar 

  89. Fearon KCH. Cancer cachexia: developing multimodal therapy for a multidimensional problem. Eur J Cancer. 2008;44:1124–32.

    Article  CAS  PubMed  Google Scholar 

  90. Miller LD, Smeds J, George J, Vega VB, Vergara L, Ploner A, et al. An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. Proc Natl Acad Sci U S A. 2005;102:17882 (vol 102, pg 13550, 2005).

    CAS  Google Scholar 

  91. Milanezi F, Carvalho S, Schmitt FC. EGFR/HER2 in breast cancer: a biological approach for molecular diagnosis and therapy. Expert Rev Mol Diagn. 2008;8:417–34.

    Article  CAS  PubMed  Google Scholar 

  92. Soares-Maia R, Faustino-Rocha AI, Teixeira-Guedes CI, Pinho-Oliveira J, Talhada D, Rema A, et al. MNU-induced rat mammary carcinomas: immunohistology and estrogen receptor expression. J Environ Pathol Toxicol. 2013;32:157–63.

    Article  CAS  Google Scholar 

  93. Thompson HJ, McGinley JN, Rothhammer K, Singh M. Rapid induction of mammary intraductal proliferations, ductal carcinoma in-situ and carcinomas by the injection of sexually immature female rats with 1-methyl-1-nitrosourea. Carcinogenesis. 1995;16:2407–11.

    Article  CAS  PubMed  Google Scholar 

  94. Welsch CW. Host factors affecting the growth of carcinogen-induced rat mammary carcinomas—a review and tribute to Huggins, Charles, Brenton. Cancer Res. 1985;45:3415–43.

    CAS  PubMed  Google Scholar 

  95. Rivera ES, Andrade N, Martin G, Melito G, Cricco G, Mohamad N, et al. Induction of mammary tumors in rat by intraperitoneal injection of NMU—histopathology and estrous cycle influence. Cancer Lett. 1994;86:223–8.

    Article  CAS  PubMed  Google Scholar 

  96. Rose DP, Pruitt B, Stauber P, Erturk E, Bryan GT. Influence of dosage schedule on the biological characteristics of N-nitrosomethylurea-induced rat mammary tumors. Cancer Res. 1980;40:235–9.

    CAS  PubMed  Google Scholar 

  97. Thompson HJ, Adlakha H. Dose-responsive induction of mammary gland carcinomas by the intraperitoneal injection of 1-methyl-1-nitrosourea. Cancer Res. 1991;51:3411–5.

    CAS  PubMed  Google Scholar 

  98. Rizza P, Barone I, Zito D, Giordano F, Lanzino M, De Amicis F, Mauro L, Sisci D, Catalano S, Wright KD, Gustafsson JA, Ando S. Estrogen receptor beta as a novel target of androgen receptor action in breast cancer cell lines. Breast Cancer Res. 2014;16.

  99. Leygue E, Murphy LC. A bi-faceted role of estrogen receptor beta in breast cancer. Endocr Relat Cancer. 2013;20:R127–39.

    Article  CAS  PubMed  Google Scholar 

  100. Powell E, Shanle E, Brinkman A, Li J, Keles S, Wisinski KB, Huang W, Xu W. Identification of estrogen receptor dimer selective ligands reveals growth-inhibitory effects on cells that co-express ER alpha and ER beta. Plos One. 2012;7.

  101. Shanle EK, Xu W. Selectively targeting estrogen receptors for cancer treatment. Adv Drug Deliv Rev. 2010;62:1265–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Rastelli F, Crispino S. Factors predictive of response to hormone therapy in breast cancer. Tumori. 2008;94:370–83.

    PubMed  Google Scholar 

  103. Ma CX, Sanchez CG, Ellis MJ. Predicting endocrine therapy responsiveness in breast cancer. Oncology-NY. 2009;23:133–42.

    Google Scholar 

  104. Ali SH, O'Donnell AL, Balu D, Pohl MB, Seyler MJ, Mohamed S, et al. Estrogen receptor-alpha in the inhibition of cancer growth and angiogenesis. Cancer Res. 2000;60:7094–8.

    CAS  PubMed  Google Scholar 

  105. Gruvberger-Saal SK, Bendahl PO, Saal LH, Laakso M, Hegardt C, Eden P, et al. Estrogen receptor beta expression is associated with tamoxifen response in ER alpha-negative breast carcinoma. Clin Cancer Res. 2007;13:1987–94.

    Article  CAS  PubMed  Google Scholar 

  106. Fleming FJ, Hill ADK, McDermott EW, O'Higgins NJ, Young LS. Differential recruitment of coregulator proteins steroid receptor coactivator-1 and silencing mediator for retinoid and thyroid receptors to the estrogen receptor-estrogen response element by beta-estradiol and 4-hydroxytamoxifen in human breast cancer. J Clin Endocrinol Metab. 2004;89:375–83.

    Article  CAS  PubMed  Google Scholar 

  107. Esslimani-Sahla M, Simony-Lafontaine J, Kramar A, Lavaill R, Mollevi C, Warner M, et al. Estrogen receptor beta (ER beta) level but not its ER beta cx variant helps to predict tamoxifen resistance in breast cancer. Clin Cancer Res. 2004;10:5769–76.

    Article  CAS  PubMed  Google Scholar 

  108. Shaaban AM, Green AR, Karthik S, Alizadeh Y, Hughes TA, Harkins L, et al. Nuclear and cytoplasmic expression of ER beta 1, ER beta 2, and ER beta 5 identifies distinct prognostic outcome for breast cancer patients. Clin Cancer Res. 2008;14:5228–35.

    Article  CAS  PubMed  Google Scholar 

  109. Saji S, Omoto Y, Shimizu C, Warner M, Hayashi Y, Horiguchi S, et al. Expression of estrogen receptor (ER) beta cx protein in ER alpha-positive breast cancer: specific correlation with progesterone receptor. Cancer Res. 2002;62:4849–53.

    CAS  PubMed  Google Scholar 

  110. O'Neill PA, Davies MPA, Shaaban AM, Innes H, Torevell A, Sibson DR, et al. Wild-type oestrogen receptor beta (ERb1) mRNA and protein expression in tamoxifen-treated post-menopausal breast cancers. Br J Cancer. 2004;91:1694–702.

    PubMed  PubMed Central  Google Scholar 

  111. Novelli F, Milella M, Melucci E, Di Benedetto A, Sperduti I, Perrone-Donnorso R, Perracchio L, Venturo I, Nistico C, Fabi A, Buglioni S, Natali PG, Mottolese M. A divergent role for estrogen receptor-beta in node-positive and node-negative breast cancer classified according to molecular subtypes: an observational prospective study. Breast Cancer Res. 2008;10.

  112. Lu Y, You M, Ghazoui Z, Liu PY, Vedell PT, Wen WD, et al. Concordant effects of aromatase inhibitors on gene expression in ER+ rat and human mammary cancers and modulation of the proteins coded by these genes. Cancer Prev Res. 2013;6:1151–61.

    Article  CAS  Google Scholar 

  113. Howe LR, Brown PH. Targeting the HER/EGFR/ErbB family to prevent breast cancer. Cancer Prev Res. 2011;4:1149–57.

    Article  CAS  Google Scholar 

  114. Arteaga CL, Moulder SL, Yakes FM. HER (erbB) tyrosine kinase inhibitors in the treatment of breast cancer. Semin Oncol. 2002;29:4–10.

    Article  CAS  PubMed  Google Scholar 

  115. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, Mcguire WL. Human breast cancer—correlation of relapse and survival with amplification of the Her-2 Neu oncogene. Science. 1987;235:177–82.

    Article  CAS  PubMed  Google Scholar 

  116. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001;98:10869–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Grant S. Cotargeting survival signaling pathways in cancer. J Clin Invest. 2008;118:3003–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EWT, Chang F, et al. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. BBA Mol Cell Res. 2007;1773:1263–84.

    CAS  Google Scholar 

  119. Dineva IK, Zaharieva MM, Konstantinov SM, Eibl H, Berger MR. Erufosine suppresses breast cancer in vitro and in vivo for its activity on PI3K, c-Raf and Akt proteins. J Cancer Res Clin Oncol. 2012;138:1909–17.

    Article  CAS  PubMed  Google Scholar 

  120. McLaughlin SK, Olsen SN, Dake B, De Raedt T, Lim E, Bronson RT, et al. The RasGAP gene, RASAL2, is a tumor and metastasis suppressor. Cancer Cell. 2013;24:365–78.

    Article  CAS  PubMed  Google Scholar 

  121. Zarbl H, Sukumar S, Arthur AV, Martinzanca D, Barbacid M. Direct mutagenesis of Ha-Ras-1 oncogenes by N-nitroso-N-methylurea during initiation of mammary carcinogenesis in rats. Nature. 1985;315:382–5.

    Article  CAS  PubMed  Google Scholar 

  122. Sukumar S, Notario V, Martinzanca D, Barbacid M. Induction of mammary carcinomas in rats by nitroso-methylurea involves malignant activation of H-Ras-1 locus by single point mutations. Nature. 1983;306:658–61.

    Article  CAS  PubMed  Google Scholar 

  123. Lacroix M, Linares LK, Le Cam L. Role of the p53 tumor suppressor in metabolism. Med Sci. 2013;29:1125–30.

    Google Scholar 

  124. Ogawa K, Tokusashi Y, Fukuda I. Absence of p53 mutations in methylnitrosourea-induced mammary tumors in rats. Cancer Detect Prev. 1996;20:214–7.

    CAS  PubMed  Google Scholar 

  125. Asamoto M, Ochiya T, Toriyama-Baba H, Ota T, Sekiya T, Terada M, et al. Transgenic rats carrying human c-Ha-ras proto-oncogenes are highly susceptible to N-methyl-N-nitrosourea mammary carcinogenesis. Carcinogenesis. 2000;21:243–9.

    Article  CAS  PubMed  Google Scholar 

  126. Kito K, Kihana T, Sugita A, Murao S, Akehi S, Sato M, et al. Incidence of p53 and Ha-ras gene mutations in chemically induced rat mammary carcinomas. Mol Carcinog. 1996;17:78–83.

    Article  CAS  PubMed  Google Scholar 

  127. Toker A, Yoeli-Lerner M. Akt signaling and cancer: surviving but not moving on. Cancer Res. 2006;66:3963–6.

    Article  CAS  PubMed  Google Scholar 

  128. Wazir U, Wazir A, Khanzada ZS, Jiang WG, Sharma AK, Mokbel K. Current state of mTOR targeting in human breast cancer. Cancer Genomics Proteomics. 2014;11:167–74.

    PubMed  Google Scholar 

  129. Toschi A, Lee E, Thompson S, Gadir N, Yellen P, Drain CM, et al. Phospholipase D-mTOR requirement for the Warburg effect in human cancer cells. Cancer Lett. 2010;299:72–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149:274–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. McDonald PC, Oloumi A, Mills J, Dobreva I, Maidan M, Gray V, et al. Rictor and integrin-linked kinase interact and regulate Akt phosphorylation and cancer cell survival. Cancer Res. 2008;68:1618–24.

    Article  CAS  PubMed  Google Scholar 

  132. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307:1098–101.

    Article  CAS  PubMed  Google Scholar 

  133. Feng ZH, Zhang H, Levine AJ, Jin S. The coordinate regulation of the p53 and rnTOR pathways in cells. Proc Natl Acad Sci U S A. 2005;102:8204–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer. 2006;6:729–34.

    Article  CAS  PubMed  Google Scholar 

  135. Schmelzle T, Hall MN. TOR, a central controller of cell growth. Cell. 2000;103:253–62.

    Article  CAS  PubMed  Google Scholar 

  136. Inoki K, Corradetti MN, Guan KL. Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet. 2005;37:19–24.

    Article  CAS  PubMed  Google Scholar 

  137. Mita M, Mita A, Rowinsky E. Mammalian target of rapamycin: a new molecular target for breast cancer. Clin Breast Cancer. 2003;4:126–37.

    Article  CAS  PubMed  Google Scholar 

  138. Arumugam A, Parada J, Rajkumar L. Mammary cancer promotion by ovarian hormones involves IGFR/AKT/mTOR signaling. Steroids. 2012;77:791–7.

    Article  CAS  PubMed  Google Scholar 

  139. Hardie DG. AMP-activated protein kinase: the guardian of cardiac energy status. J Clin Invest. 2004;114:465–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Hardie DG. The AMP-activated protein kinase pathway—new players upstream and downstream. J Cell Sci. 2004;117:5479–87.

    Article  CAS  PubMed  Google Scholar 

  141. Hardie DG. New roles for the LKB1 -> AMPK pathway. Curr Opin Cell Biol. 2005;17:167–73.

    Article  CAS  PubMed  Google Scholar 

  142. Hardie DG. AMPK: a key regulator of energy balance in the single cell and the whole organism. Int J Obes. 2008;32:S7–12.

    Article  CAS  Google Scholar 

  143. Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011;12:21–35.

    Article  CAS  PubMed  Google Scholar 

  144. Efeyan A, Sabatini DM. mTOR and cancer: many loops in one pathway. Curr Opin Cell Biol. 2010;22:169–76.

    Article  CAS  PubMed  Google Scholar 

  145. Kahn BB, Alquier T, Carling D, Hardie DG. AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 2005;1:15–25.

    Article  CAS  PubMed  Google Scholar 

  146. Kemp BE, Stapleton D, Campbell DJ, Chen ZP, Murthy S, Walter M, et al. AMP-activated protein kinase, super metabolic regulator. Biochem Soc Trans. 2003;31:162–8.

    Article  CAS  PubMed  Google Scholar 

  147. Motoshima H, Goldstein BJ, Igata M, Araki E. AMPK and cell proliferation—AMPK as a therapeutic target for atherosclerosis and cancer. J Physiol Lond. 2006;574:63–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Zhu Z, Iang W, Thompson M, McGinley J, Thompson H. Metformin as an energy restriction mimetic agent for breast cancer prevention. J Carcinog. 2011;10:17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Qiu F, Ray P, Brown K, Barker PE, Jhanwar S, Ruddle FH, et al. Primary structure of c-kit—relationship with the Csf-1/Pdgf receptor kinase family oncogenic activation of V-Kit involves deletion of extracellular domain and C-terminus. EMBO J. 1988;7:1003–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Bernex F, DeSepulveda P, Kress C, Elbaz C, Delouis C, Panthier JJ. Spatial and temporal patterns of c-kit-expressing cells in W-lacZ/+ and W-lacZ/W-lacZ mouse embryos. Development. 1996;122:3023–33.

    CAS  PubMed  Google Scholar 

  151. Natali PG, Nicotra MR, Sures I, Santoro E, Bigotti A, Ullrich A. Expression of c-kit receptor in normal and transformed human nonlymphoid tissues. Cancer Res. 1992;52:6139–43.

    CAS  PubMed  Google Scholar 

  152. Matsuda R, Takahashi T, Nakamura S, Sekido Y, Nishida K, Seto M, et al. Expression of the c-kit protein in human solid tumors and in corresponding fetal and adult normal tissues. Am J Pathol. 1993;142:339–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Natali PG, Nicotra MR, Sures I, Mottolese M, Botti C, Ullrich A. Breast cancer is associated with loss of the c-kit oncogene product. Int J Cancer. 1992;52:713–7.

    Article  CAS  PubMed  Google Scholar 

  154. Chui X, Egami H, Yamashita J, Kurizaki T, Ohmachi H, Yamamoto S, et al. Immunohistochemical expression of the c-kit proto-oncogene product in human malignant and non-malignant breast tissues. Br J Cancer. 1996;73:1233–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Maffini MV, Soto AM, Sonnenschein C, Papadopoulos N, Theoharides TC. Lack of c-kit receptor promotes mammary tumors in N-nitrosomethylurea-treated Ws/Ws rats. Cancer Cell Int. 2008;8.

  156. Folkman J. What is the evidence that tumors are angiogenesis dependent. J Natl Cancer Inst. 1990;82:4–6.

    Article  CAS  PubMed  Google Scholar 

  157. Folkman J, Bach M, Rowe JW, Davidoff F, Lambert P, Hirsch C, et al. Tumor angiogenesis—therapeutic implications. N Engl J Med. 1971;285:1182–6.

    Article  CAS  PubMed  Google Scholar 

  158. Weidner N. Tumor angiogenesis—review of current applications in tumor prognostication. Semin Diagn Pathol. 1993;10:302–13.

    CAS  PubMed  Google Scholar 

  159. Relf M, LeJeune S, Scott PAE, Fox S, Smith K, Leek R, et al. Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res. 1997;57:963–9.

    CAS  PubMed  Google Scholar 

  160. Yoshiji H, Gomez DE, Shibuya M, Thorgeirsson UP. Expression of vascular endothelial growth factor, its receptor, and other angiogenic factors in human breast cancer. Cancer Res. 1996;56:2013–6.

    CAS  PubMed  Google Scholar 

  161. Obermair A, Obruca A, Pohl M, Kaider A, Vales A, Leodolter S, et al. Vascular endothelial growth factor and its receptors in male fertility. Fertil Steril. 1999;72:269–75.

    Article  CAS  PubMed  Google Scholar 

  162. Saminathan M, Rai R, Dhama K, Ranganath G, Murugesan V, Kannan K, et al. Histopathology and immunohistochemical expression of N-methyl-N-nitrosourea (NMU) induced mammary tumours in Sprague-Dawley rats. Asian J Anim Vet Adv. 2014;9:621–40.

    Article  Google Scholar 

  163. Massague J, Gomis RR. The logic of TGF beta signaling. FEBS Lett. 2006;580:2811–20.

    Article  CAS  PubMed  Google Scholar 

  164. Taylor MA, Lee YH, Schiemann WP. Role of TGF-beta and the tumor microenvironment during mammary tumorigenesis. Gene Expr. 2011;15:117–32.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Massague J. TGF beta in cancer. Cell. 2008;134:215–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Tian MZ, Neil JR, Schiemann WP. Transforming growth factor-beta and the hallmarks of cancer. Cell Signal. 2011;23:951–62.

    Article  CAS  PubMed  Google Scholar 

  167. Bierie B, Moses H. Tumour microenvironment: TGFb: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer. 2006;6:506–20.

    Article  CAS  PubMed  Google Scholar 

  168. Thompson HJ, Singh M. Rat models of premalignant breast disease. J Mammary Gland Biol Neoplasia. 2000;5:409–20.

    Article  CAS  PubMed  Google Scholar 

  169. Ouban A, Muraca P, Yeatman T, Coppola D. Expression and distribution of insulin-like growth factor-1 receptor in human carcinomas. Hum Pathol. 2003;34:803–8.

    Article  CAS  PubMed  Google Scholar 

  170. Shimizu C, Hasegawa T, Tani Y, Takahashi F, Takeuchi M, Watanabe T, et al. Expression of insulin-like growth factor 1 receptor in primary breast cancer: immunohistochemical analysis. Hum Pathol. 2004;35:1537–42.

    Article  CAS  PubMed  Google Scholar 

  171. Yerushalmi R, Gelmon KA, Leung S, Gao DX, Cheang M, Pollak M, et al. Insulin-like growth factor receptor (IGF-1R) in breast cancer subtypes. Breast Cancer Res Treat. 2012;132:131–42.

    Article  CAS  PubMed  Google Scholar 

  172. Gasco M, Shami S, Crook T. The p53 pathway in breast cancer. Breast Cancer Res. 2002;4:70–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Hollstein M, Sidransky D, Vogelstein B, Harris CC. P53 mutations in human cancers. Science. 1991;253:49–53.

    Article  CAS  PubMed  Google Scholar 

  174. Pharoah PDP, Day NE, Caldas C. Somatic mutations in the p53 gene and prognosis in breast cancer: a meta-analysis. Br J Cancer. 1999;80:1968–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Phillips KA, Nichol K, Ozcelik H, Knight J, Done SJ, Goodwin PJ, et al. Frequency of p53 mutations in breast carcinomas from Ashkenazi Jewish carriers of BRCA1 mutations. J Natl Cancer Inst. 1999;91:469–73.

    Article  CAS  PubMed  Google Scholar 

  176. Smith PD, Crossland S, Parker G, Osin P, Brooks L, Waller J, et al. Novel p53 mutants selected in BRCA-associated tumours which dissociate transformation suppression from other wild-type p53 functions. Oncogene. 1999;18:2451–9.

    Article  CAS  PubMed  Google Scholar 

  177. Antoniou AC, Easton DF. Models of genetic susceptibility to breast cancer. Oncogene. 2006;25:5898–905.

    Article  CAS  PubMed  Google Scholar 

  178. Levy-Lahad E, Plon SE. A risky business—assessing breast cancer risk. Science. 2003;302:574–5.

    Article  CAS  PubMed  Google Scholar 

  179. King MC, Marks JH, Mandell JB. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003;302:643–6.

    Article  CAS  PubMed  Google Scholar 

  180. Narod SA, Foulkes WD. BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer. 2004;4:665–76.

    Article  CAS  PubMed  Google Scholar 

  181. Greenblatt MS, Bennett WP, Hollstein M, Harris CC. Mutations in the P53 tumor-suppressor gene—clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994;54:4855–78.

    CAS  PubMed  Google Scholar 

  182. Lloyd DR, Hanawalt PC. p53-dependent global genomic repair of benzo[a]pyrene-7,8-diol-9,10-epoxide adducts in human cells. Cancer Res. 2000;60:517–21.

    CAS  PubMed  Google Scholar 

  183. Miyashita T, Krajewski S, Krajewska M, Wang HG, Lin HK, Liebermann DA, et al. Tumor-suppressor P53 is a regulator of Bcl-2 and Bax gene-expression in-vitro and in-vivo. Oncogene. 1994;9:1799–805.

    CAS  PubMed  Google Scholar 

  184. Yonishrouach E, Resnitzky D, Lotem J, Sachs L, Kimchi A, Oren M. Wild-type P53 induces apoptosis of myeloid leukemic cells that is inhibited by interleukin-6. Nature. 1991;352:345–7.

    Article  CAS  Google Scholar 

  185. Oster SK, Ho CSW, Soucie EL, Penn LZ. The myc oncogene: (M)under-bar-arvelousl(Y)under-bar (C)under-bar-omplex. Adv Cancer Res. 2002;84:81–154.

    Article  CAS  PubMed  Google Scholar 

  186. Evan G. Taking a back door to target Myc. Science. 2012;335:293–4.

    Article  CAS  PubMed  Google Scholar 

  187. Eisenman R. The Myc oncogene. Berlin: Springer; 2006.

    Google Scholar 

  188. Cowling VH, D'Cruz CM, Chodosh LA. Cole MD: c-Myc transforms human mammary epithelial cells through repression of the Wnt inhibitors DKK1 and SFRP1. Mol Cell Biol. 2007;27:5135–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Barathidasan R, Pawaiya RS, Rai RB, Dhama K. Upregulated Myc expression in N-methyl nitrosourea (MNU)-induced rat mammary tumours. Asian Pac J Cancer Prev. 2013;14:4883–9.

    Article  PubMed  Google Scholar 

  190. Hunter T, Pines J. Cyclins and cancer. 2. Cyclin-D and Cdk inhibitors come of age. Cell. 1994;79:573–82.

    Article  CAS  PubMed  Google Scholar 

  191. Sgambato A, Han EKH, Zhang YJ, Moon RC, Santella RM, Weinstein IB. Deregulated expression of cyclin D1 and other cell cycle-related genes in carcinogen-induced rat mammary tumors. Carcinogenesis. 1995;16:2193–8.

    Article  CAS  PubMed  Google Scholar 

  192. Devilee P, Schuuring E, Vandevijver MJ, Cornelisse CJ. Recent developments in the molecular-genetic understanding of breast cancer. Crit Rev Oncog. 1994;5:247–70.

    Article  CAS  PubMed  Google Scholar 

  193. Russo J, Russo IH. Mammary tumorigenesis. Prog Exp Tumor Res. 1991;33:175–91.

    Article  CAS  PubMed  Google Scholar 

  194. Zhu ZJ, Jiang WQ, Thompson HJ. Effect of energy restriction on the expression of cyclin D1 and p27 during premalignant and malignant stages of chemically induced mammary carcinogenesis. Mol Carcinog. 1999;24:241–5.

    Article  CAS  PubMed  Google Scholar 

  195. Cooper D, Schermer A, Sun TT. Classification of human epithelia and their neoplasms using monoclonal antibodies to keratins—strategies, applications, and limitations. Lab Investig. 1985;52:243–56.

    CAS  PubMed  Google Scholar 

  196. Nagle RB, Bocker W, Davis JR, Heid HW, Kaufmann M, Lucas DO, et al. Characterization of breast carcinomas by 2 monoclonal antibodies distinguishing myoepithelial from luminal epithelial cells. J Histochem Cytochem. 1986;34:869–81.

    Article  CAS  PubMed  Google Scholar 

  197. Debus E, Weber K, Osborn M. Monoclonal cytokeratin antibodies that distinguish simple from stratified squamous epithelia—characterization on human tissues. EMBO J. 1982;1:1641–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Malzahn K, Mitze M, Thoenes M, Moll R. Biological and prognostic significance of stratified epithelial cytokeratins in infiltrating ductal breast carcinomas. Virchows Arch. 1998;433:119–29.

    Article  CAS  PubMed  Google Scholar 

  199. Rejthar A, Nenutil R. The intermediate filaments and prognostically oriented morphological classification in ductal breast carcinoma. Neoplasma. 1997;44:370–3.

    CAS  PubMed  Google Scholar 

  200. van de Rijn M, Perou CM, Tibshirani R, Haas P, Kallioniemi C, Kononen J, et al. Expression of cytokeratins 17 and 5 identifies a group of breast carcinomas with poor clinical outcome. Am J Pathol. 2002;161:1991–6.

    Article  PubMed  PubMed Central  Google Scholar 

  201. Santini D, Ceccarelli C, Taffurelli M, Pileri S, Marrano D. Differentiation pathways in primary invasive breast carcinoma as suggested by intermediate filament and biopathological marker expression. J Pathol. 1996;179:386–91.

    Article  CAS  PubMed  Google Scholar 

  202. Wetzels RHW, Kuijpers HJH, Lane EB, Leigh IM, Troyanovsky SM, Holland R, et al. Basal cell-specific and hyperproliferation-related keratins in human breast cancer. Am J Pathol. 1991;138:751–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Altmannsberger M, Dirk T, Droese M, Weber K, Osborn M. Keratin polypeptide distribution in benign and malignant breast tumors—subdivision of ductal carcinomas using monoclonal antibodies. Virchows Arch. 1986;51:265–75.

    Article  CAS  Google Scholar 

  204. El-Rehim DMA, Pinder SE, Paish CE, Bell J, Blamey R, Robertson JFR, et al. Expression of luminal and basal cytokeratins in human breast carcinoma. J Pathol. 2004;203:661–71.

    Article  Google Scholar 

  205. Lu JX, Pei HY, Kaeck M, Thompson HJ. Gene expression changes associated with chemically induced rat mammary carcinogenesis. Mol Carcinog. 1997;20:204–15.

    Article  CAS  PubMed  Google Scholar 

  206. Goepfert TM, Moreno-Smith M, Edwards DG, Pathak S, Medina D, Brinkley WR. Loss of chromosomal integrity drives rat mammary tumorigenesis. Int J Cancer. 2007;120:985–94.

    Article  CAS  PubMed  Google Scholar 

  207. Sharma D, Smits BMG, Eichelberg MR, Meilahn AL, Muelbl MJ, Haag JD, Gould MN. Quantification of epithelial cell differentiation in mammary glands and carcinomas from DMBA- and MNU-exposed rats. Plos One. 2011;6.

  208. Tsukamoto R, Mikami T, Miki K, Uehara N, Yuri T, Matsuoka Y, et al. N-methyl-N-nitrosourea-induced mammary carcinogenesis is promoted by short-term treatment with estrogen and progesterone mimicking pregnancy in aged female Lewis rats. Oncol Rep. 2007;18:337–42.

    PubMed  Google Scholar 

  209. Sreenath T, Matrisian LM, Stetlerstevenson W, Gattonicelli S, Pozzatti RO. Expression of matrix metalloproteinase genes in transformed rat cell lines of high and low metastatic potential. Cancer Res. 1992;52:4942–7.

    CAS  PubMed  Google Scholar 

  210. Duffy MJ. The role of proteolytic enzymes in cancer invasion and metastasis. Clin Exp Metastasis. 1992;10:145–55.

    Article  CAS  PubMed  Google Scholar 

  211. Nagase H, Woessner JF. Matrix metalloproteinases. J Biol Chem. 1999;274:21491–4.

    Article  CAS  PubMed  Google Scholar 

  212. Nabeshima K, Inoue T, Shimao Y, Sameshima T. Matrix metalloproteinases in tumor invasion: role for cell migration. Pathol Int. 2002;52:255–64.

    Article  CAS  PubMed  Google Scholar 

  213. Kousidou OC, Roussidis AE, Theocharis AD, Karamanos NK. Expression of MMPs and TIMPs genes in human breast cancer epithelial cells depends on cell culture conditions and is associated with their invasive potential. Anticancer Res. 2004;24:4025–30.

    CAS  PubMed  Google Scholar 

  214. Bartsch JE, Staren ED, Appert HE. Matrix metalloproteinase expression in breast cancer. J Surg Res. 2003;110:383–92.

    Article  CAS  PubMed  Google Scholar 

  215. Roomi MW, Roomi NW, Ivanov V, Kalinovsky T, Niedzwiecki A, Rath M. Modulation of N-methyl-N-nitrosourea induced mammary tumors in Sprague-Dawley rats by combination of lysine, proline, arginine, ascorbic acid and green tea extract. Breast Cancer Res. 2005;7:R291–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Steele VE, Lubet RA. The use of animal models for cancer chemoprevention drug development. Semin Oncol. 2010;37:327–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Ahelm C, Frincke J, White S, Reading C, TRauger R, Lakshmanaswamy R. 17a-Ethynyl-5a-androstane-3a, 17a-diol treatment of MNU-induced mammary cancer in rats. Int J Breast Cancer. 2011;2011:1–9.

    Article  CAS  Google Scholar 

  218. Moon RC, Mehta RG. Chemoprevention of experimental carcinogenesis in animals. Prev Med. 1989;18:576–91.

    Article  CAS  PubMed  Google Scholar 

  219. Faustino-Rocha AI, Silva A, Gabriel J, Teixeira-Guedes CI, Lopes C, da Costa RG, et al. Ultrasonographic, thermographic and histologic evaluation of MNU-induced mammary tumors in female Sprague-Dawley rats. Biomed Pharmacother. 2013;67:771–6.

    Article  CAS  PubMed  Google Scholar 

  220. Kahn LH. Confronting zoonoses, linking human and veterinary medicine. Emerg Infect Dis. 2006;12:556–61.

    Article  PubMed  PubMed Central  Google Scholar 

  221. Enserink M. Medicine—initiative aims to merge animal and human health science to benefit both. Science. 2007;316:1553.

    Article  CAS  PubMed  Google Scholar 

  222. Cardiff R. Epilog: comparative medicine, one medicine and genomic pathology. Breast Dis. 2007;28:107–10.

    Article  PubMed  Google Scholar 

  223. Badawi AF, Eldeen MB, Liu YY, Ross EA, Badr MZ. Inhibition of rat mammary gland carcinogenesis by simultaneous targeting of cyclooxygenase-2 and peroxisome proliferator-activated receptor gamma. Cancer Res. 2004;64:1181–9 (Retracted article. See vol. 65, pp. 8057, 2005).

    Article  CAS  PubMed  Google Scholar 

  224. Kubatka P, Ahlers I, Ahlersova E, Adamekova E, Luk P, Bojkova B, et al. Chemoprevention of mammary carcinogenesis in female rats by rofecoxib. Cancer Lett. 2003;202:131–6.

    Article  CAS  PubMed  Google Scholar 

  225. Mccormick DL, Adamowski CB, Fiks A, Moon RC. Lifetime dose-response relationships for mammary-tumor induction by a single administration of N-methyl-N-nitrosourea. Cancer Res. 1981;41:1690–4.

    CAS  PubMed  Google Scholar 

  226. Mehta RG. Experimental basis for the prevention of breast cancer. Eur J Cancer. 2000;36:1275–82.

    Article  CAS  PubMed  Google Scholar 

  227. Singh M, McGinley JN, Thompson HJ. A comparison of the histopathology of premalignant and malignant mammary gland lesions induced in sexually immature rats with those occurring in the human. Lab Investig. 2000;80:221–31.

    Article  CAS  PubMed  Google Scholar 

  228. Thompson HJ, McGinley J, Rothhammer K, Singh M. Ovarian hormone dependence of pre-malignant and malignant mammary gland lesions induced in pre-pubertal rats by 1-methyl-1-nitrosourea. Carcinogenesis. 1998;19:383–6.

    Article  CAS  PubMed  Google Scholar 

  229. National Cancer Institute at the National Institutes of Health: Drugs approved for breast cancer. http://www.cancer.gov.

  230. Bera TK, Tsukamoto T, Panda DK, Huang T, Guzman RC, Hwang SI, et al. Defective retrovirus insertion activates c-Ha-ras protooncogene in an MNU-induced rat mammary carcinoma. Biochem Biophys Res Commun. 1998;248:835–40.

    Article  CAS  PubMed  Google Scholar 

  231. Bigsby RA. Synergistic tumor promoter effects of estrone and progesterone in methylnitrosourea-induced rat mammary cancer. Cancer Lett. 2002;179:113–9.

    Article  CAS  PubMed  Google Scholar 

  232. Garcia-Solis P, Alfaro Y, Anguiano B, Delgado G, Guzman RC, Nandi S, et al. Inhibition of N-methyl-N-nitrosourea-induced mammary carcinogenesis by molecular iodine(I-2) but not by iodide (I-) treatment evidence that I-2 prevents cancer promotion. Mol Cell Endocrinol. 2005;236:49–57.

    Article  CAS  PubMed  Google Scholar 

  233. Grubbs CJ, Hill DL, Bland KI, Beenken SW, Lin TH, Eto I, et al. 9cUAB30, an RXR specific retinoid, and/or tarnoxifen in the prevention of methylnitrosourea-induced mammary cancers. Cancer Lett. 2003;201:17–24.

    Article  CAS  PubMed  Google Scholar 

  234. Imai T, Cho YM, Hasumura M, Hirose M. Enhancement by acrylamide of N-methyl-N-nitrosourea-induced rat mammary tumor development - possible application for a model to detect co-modifiers of carcinogenesis. Cancer Lett. 2005;230:25–32.

    Article  CAS  PubMed  Google Scholar 

  235. Li JX, Cho YY, Langfald A, Carper A, Lubet RA, Grubbs CJ, et al. Lapatinib, a preventive/therapeutic agent against mammary cancer, suppresses RTK-mediated signaling through multiple signaling pathways. Cancer Prev Res. 2011;4:1190–7.

    Article  CAS  Google Scholar 

  236. Liska J, Macejova D, Galbavy S, Baranova M, Zlatos J, Stvrtina S, et al. Treatment of 1-methyl-1-nitrosourea-induced mammary tumours with immunostimulatory CpG motifs and 13-cis retinoic acid in female rats: histopathological study. Exp Toxicol Pathol. 2003;55:173–9.

    Article  CAS  PubMed  Google Scholar 

  237. Mccormick DL, Moon RC. Inhibition of mammary carcinogenesis by flurbiprofen, a non-steroidal antiinflammatory agent. Br J Cancer. 1983;48:859–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Mehta R, Hawthorne M, Uselding L, Albinescu D, Moriarty R, Christov K, et al. Prevention of N-methyl-N-nitrosourea-induced mammary carcinogenesis in rats by 1 alpha-hydroxyvitamin D-5. J Natl Cancer Inst. 2000;92:1836–40.

    Article  CAS  PubMed  Google Scholar 

  239. Nakhate KT, Kokare DM, Singru PS, Taksande AG, Kotwal SD, Subhedar NK. Hypothalamic cocaine- and amphetamine-regulated transcript peptide is reduced and fails to modulate feeding behavior in rats with chemically-induced mammary carcinogenesis. Pharmacol Biochem Behav. 2010;97:340–9.

    Article  CAS  PubMed  Google Scholar 

  240. Schaffer EM, Liu JZ, Green J, Dangler CA, Milner JA. Garlic and associated allyl sulfur components inhibit N-methyl-N-nitrosourea induced rat mammary carcinogenesis. Cancer Lett. 1996;102:199–204.

    Article  CAS  PubMed  Google Scholar 

  241. Shirai K, Uemura Y, Fukumoto M, Tsukamoto T, Pascual R, Nandi S, et al. Synergistic effect of MNU and DMBA in mammary carcinogenesis and H-ras activation in female Sprague-Dawley rats. Cancer Lett. 1997;120:87–93.

    Article  CAS  PubMed  Google Scholar 

  242. Thompson HJ, Meeker LD. Induction of mammary-gland carcinomas by the subcutaneous injection of 1-methyl-1-nitrosourea. Cancer Res. 1983;43:1628–9.

    CAS  PubMed  Google Scholar 

  243. Yang JH, Nakagawa H, Tsuta K, Tsubura A. Influence of perinatal genistein exposure on the development of MNU-induced mammary carcinoma in female Sprague-Dawley rats. Cancer Lett. 2000;149:171–9.

    Article  CAS  PubMed  Google Scholar 

  244. Shivapurkar N, Tang ZC, Frost A, Alabaster O. A rapid dual organ rat carcinogenesis bioassay for evaluating the chemoprevention of breast and colon cancer. Cancer Lett. 1996;100:169–79.

    Article  CAS  PubMed  Google Scholar 

  245. Lee WM, Lu SY, Medline A, Archer MC. Susceptibility of lean and obese Zucker rats to tumorigenesis induced by N-methyl-N-nitrosourea. Cancer Lett. 2001;162:155–60.

    Article  CAS  PubMed  Google Scholar 

  246. Coburn MA, Brueggemann S, Bhatia S, Cheng B, Li BDL, Li XL, et al. Establishment of a mammary carcinoma cell line from Syrian hamsters treated with N-methyl-N-nitrosourea. Cancer Lett. 2011;312:82–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Mori H, Niwa K, Zheng Q, Yamada Y, Sakata K, Yoshimi N. Cell proliferation in cancer prevention; effects of preventive agents on estrogen-related endometrial carcinogenesis model and on an in vitro model in human colorectal cells. Mutat Res. 2001;480:201–7.

    Article  PubMed  Google Scholar 

  248. Niwa K, Morishita S, Murase T, Mudigdo A, Tanaka T, Mori H, et al. Chronological observation of mouse endometrial carcinogenesis induced by N-methyl-N-nitrosourea and 17 beta-estradiol. Cancer Lett. 1996;104:115–9.

    Article  CAS  PubMed  Google Scholar 

  249. Gonçalves B, Zanetoni C, Scarano W, Góes R, Vilamaior P, Taboga S, et al. Prostate carcinogenesis induced by N-methyl-N-nitrosourea (MNU) in gerbils: histopathological diagnosis and potential invasiveness mediated by extracellular matrix components. Exp Mol Pathol. 2010;88:96–106.

    Article  PubMed  CAS  Google Scholar 

  250. Ordonez G, Rembao D, Sotelo J. Taenia crassiceps cysticercosis in mice does not increase the carcinogenic effect of methyl-nitrosourea. Exp Parasitol. 2003;103:169–70.

    Article  CAS  PubMed  Google Scholar 

  251. Pazos P, Lanari C, Molinolo AA. Protective role of medroxyprogesterone acetate on N-methyl-N-nitrosourea-induced lymphomas in BALB/c female mice. Leuk Res. 2001;25:165–7.

    Article  CAS  PubMed  Google Scholar 

  252. Zhang SSM, Welte T, Fu XY. Dysfunction of Stat4 leads to accelerated incidence of chemical-induced thymic lymphomas in mice. Exp Mol Pathol. 2001;70:231–8.

    Article  CAS  PubMed  Google Scholar 

  253. Hoivik DJ, Allen JS, Wall HG, Nold JB, Miller RT, Santostefano MJ. Studies evaluating the utility of N-methyl-N-nitrosourea as a positive control in carcinogenicity studies in the p53(+/-) mouse. Int J Toxicol. 2005;24:349–56.

    Article  CAS  PubMed  Google Scholar 

  254. Tarso L, Meyer F, Cioato M, Meurer L, Schirmer C. Experimental model of gastric carcinogenesis with N-methyl-nitrosourea for F344 rats and CH3 mice is valid for Wistar rats? Arq Bras Cir Dig. 2011;24:55–8.

    Article  Google Scholar 

  255. Iatropoulos MJ, Jeffrey AM, Enzmann HG, von Keutz E, Schlueter G, Williams GM. Assessment of chronic toxicity and carcinogenicity in an accelerated cancer bioassay in rats of moxifloxacin, a quinolone antibiotic. Exp Toxicol Pathol. 2001;53:345–57.

    Article  CAS  PubMed  Google Scholar 

  256. Shimizu M, Suzui M, Moriwaki H, Mori H, Yoshimi N. No involvement of beta-catenin gene mutation in gastric carcinomas induced by N-methyl-N-nitrosourea in male F344 rats. Cancer Lett. 2003;195:147–52.

    Article  CAS  PubMed  Google Scholar 

  257. Sakamoto K, Hikiba Y, Nakagawa H, Hayakawa Y, Yanai A, Akanuma M, et al. Inhibitor of kappa B kinase beta regulates gastric carcinogenesis via interleukin-1 alpha expression. Gastroenterology. 2010;139:226–U344.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Tomita H, Takaishi S, Menheniott TR, Yang XD, Shibata W, Jin GC, et al. Inhibition of gastric carcinogenesis by the hormone gastrin is mediated by suppression of TFF1 epigenetic silencing. Gastroenterology. 2011;140:879–U293.

    Article  CAS  PubMed  Google Scholar 

  259. Masui T, Tezuka N, Nakanishi H, Inada K, Miyashita N, Tatematsu M. Induction of invasive squamous cell carcinomas in the forestomach of (C3HxMSM)F1, MSM, and C3H mice by N-methyl-N-nitrosourea and mutational analysis of the H-ras and p53 genes. Cancer Lett. 1997;111:97–104.

    Article  CAS  PubMed  Google Scholar 

  260. Maruta F, Sugiyama A, Ishida K, Ikeno T, Murakami M, Kawasaki S, et al. Timing of N-methyl-N-nitrosourea administration affects gastric carcinogenesis in Mongolian gerbils infected with Helicobacter pylori. Cancer Lett. 2000;160:99–105.

    Article  CAS  PubMed  Google Scholar 

  261. Yarita T, Nettesheim P, Williams M. Tumor induction in the trachea of hamsters with N-Nitroso-N-methylurea. Cancer Res. 1978;38:1667–76.

    CAS  PubMed  Google Scholar 

  262. Tatematsu M, Yamamoto M, Iwata H, Fukami H, Yuasa H, Tezuka N, et al. Induction of glandular stomach cancers in C3H mice treated with N-methyl-N-nitrosourea in the drinking water. Jpn J Cancer Res. 1993;84:1258–64.

    Article  CAS  PubMed  Google Scholar 

  263. Shivshankar P, Devi CSS. Evaluation of co-stimulatory effects of Tamarindus indica L. on MNU-induced colonic cell proliferation. Food Chem Toxicol. 2004;42:1237–44.

    Article  CAS  PubMed  Google Scholar 

  264. Yang JH, Shikata N, Mizuoka H, Tsubura A. Colon carcinogenesis in shrews by intrarectal infusion of N-methyl-N-nitrosourea. Cancer Lett. 1996;110:105–12.

    Article  CAS  PubMed  Google Scholar 

  265. Narisawa T, Sato M, Tani M, Kudo T, Takahashi T, Goto A. Inhibition of development of methylnitrosourea-induced rat colon tumors by indomethacin treatment. Cancer Res. 1981;41:1954–7.

    CAS  PubMed  Google Scholar 

  266. Narisawa T, Takahashi M, Niwa M, Fukaura Y, Fujiki H. Inhibition of methylnitrosourea-induced large bowel cancer development in rats by sarcophytol A, a product from a marine soft coral Sarcophyton glaucum. Cancer Res. 1989;49:3287–9.

    CAS  PubMed  Google Scholar 

  267. Teixeira-Guedes C, Faustino-Rocha A, Talhada D, Duarte J, Ferreira R, Seixas F, Oliveira P. A liver schwannoma observed in a female Sprague-Dawley rat treated with MNU. Exp Toxicol Pathol. 2013.

  268. Pereira MA, Phelps JB. Promotion by dichloroacetic acid and trichloroacetic acid of N-methyl-N-nitrosourea-initiated cancer in the liver of female B6C3F1 mice. Cancer Lett. 1996;102:133–41.

    Article  CAS  PubMed  Google Scholar 

  269. Kobayashi K, Inada K, Furihata C, Tsukamoto T, Ikehara Y, Yamamoto M, et al. Effects of low dose catechol on glandular stomach carcinogenesis in BALB c mice initiated with N-methyl-N-nitrosourea. Cancer Lett. 1999;139:167–72.

    Article  CAS  PubMed  Google Scholar 

  270. Hamamoto Y, Hamamoto N, Nakajima T, Ozawa H. Morphological changes of epithelial rests of Malassez in rat molars induced by local administration of N-methylnitrosourea. Arch Oral Biol. 1998;43:899–906.

    Article  CAS  PubMed  Google Scholar 

  271. Moriguchi K, Yuri T, Yoshizawa K, Kiuchi K, Takada H, Inoue Y, et al. Dietary docosahexaenoic acid protects against N-methyl-N-nitrosourea-induced retinal degeneration in rats. Exp Eye Res. 2003;77:167–73.

    Article  CAS  PubMed  Google Scholar 

  272. Paik SS, Jeong E, Jung SW, Ha TJ, Kang S, Sim S, et al. Anthocyanins from the seed coat of black soybean reduce retinal degeneration induced by N-methyl-N-nitrosourea. Exp Eye Res. 2012;97:55–62.

    Article  CAS  PubMed  Google Scholar 

  273. Wan J, Zheng H, Chen ZL, Xiao HL, Shen ZJ, Zhou GM. Preferential regeneration of photoreceptor from Muller glia after retinal degeneration in adult rat. Vis Res. 2008;48:223–34.

    Article  CAS  PubMed  Google Scholar 

  274. Yang L, Li D, Chen JM, Yang JN, Xue LP, Hu SX, et al. Microarray expression analysis of the early N-methy-N-nitrosourea-induced retinal degeneration in rat. Neurosci Lett. 2007;418:38–43.

    Article  CAS  PubMed  Google Scholar 

  275. Rahn JJ, Trono D, Gimenez-Conti I, Butler AP, Nairn RS. Etiology of MNU-induced melanomas in Xiphophorus hybrids. Comp Biochem Physiol C. 2009;149:129–33.

    Google Scholar 

  276. Kazianis S, Gimenez-Conti I, Setlow RB, Woodhead AD, Harshbarger JC, Trono D, et al. MNU induction of neoplasia in a platyfish model. Lab Investig. 2001;81:1191–8.

    Article  CAS  PubMed  Google Scholar 

  277. Graham SD, Napalkov P, Oladele A, Keane TE, Petros JA, Clarke HS, et al. Intravesical suramin in the prevention of transitional cell carcinoma. Urology. 1995;45:59–63.

    Article  PubMed  Google Scholar 

  278. Reis LO, Ferreira U, Billis A, Cagnon VHA, Favaro WJ. Anti-angiogenic effects of the superantigen staphylococcal enterotoxin B and bacillus Calmette-Guerin immunotherapy for nonmuscle invasive bladder cancer. J Urol. 2012;187:438–45.

    Article  CAS  PubMed  Google Scholar 

  279. Wang ZG, Durand DB, Schoenberg M, Pan YT. Fluorescence guided optical coherence tomography for the diagnosis of early bladder cancer in a rat model. J Urol. 2005;174:2376–81.

    Article  CAS  PubMed  Google Scholar 

  280. Kunze E, Schulz H, Ahrens H, Gabius HJ. Lack of an antitumoral effect of immunomodulatory galactoside-specific mistletoe lectin on N-methyl-N-nitrosourea-induced urinary bladder carcinogenesis in rats. Exp Toxicol Pathol. 1997;49:167–80.

    Article  CAS  PubMed  Google Scholar 

  281. Vinodhini J, Sudha S. Effect of bis-carboxy ethyl germanium sesquoxide on N-nitroso-N-methylurea-induced rat mammary carcinoma. Asian J Pharmaceut Clin Res. 2013;6:242–4.

    CAS  Google Scholar 

  282. Kale A, Gawande S, Kotwal S, Netke S, Roomi MW, Ivanov V, et al. A combination of green tea extract, specific nutrient mixture and quercetin: An effective intervention treatment for the regression of N-methyl-N-nitrosourea (MNU)-induced mammary tumors in Wistar rats. Oncol Lett. 2010;1:313–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  283. Colston KW, Pirianov G, Bramm E, Hamberg J, Binderup L. Effects of Seocalcitol (EB1089) on nitrosomethyl urea-induced rat mammary tumors. Breast Cancer Res Treat. 2003;80:303–11.

    Article  CAS  PubMed  Google Scholar 

  284. Thompson MD, Thompson HJ, McGinley JN, Neil ES, Rush DK, Holm DG, et al. Functional food characteristics of potato cultivars (Solanum tuberosum L.): phytochemical composition and inhibition of 1-methyl-1-nitrosourea induced breast cancer in rats. J Food Compos Anal. 2009;22:571–6.

    Article  CAS  Google Scholar 

  285. Kubatka P, Sadlonová V, Kajo K, Nosalová G, Ostatnikova D, Adamicová K. Chemopreventive effects of anastrozole in a premenopausal breast cancer model. Anticancer Res. 2008;28:2819–24.

    CAS  PubMed  Google Scholar 

  286. Stearns V, Mori T, Jacobs LK, Khouri NF, Gabrielson E, Yoshida T, Kominsky SL, Huso DL, Jeter S, Powers P, Tarpinian K, Brown RJ, Lange JR, Rudek MA, Zhang Z, Tsangaris TN, Sukumar S. Preclinical and clinical evaluation of intraductally administered agents in early breast cancer. Sci Transl Med. 2011;3.

  287. Chun YS, Bisht S, Chenna V, Pramanik D, Yoshida T, Hong SM, et al. Intraductal administration of a polymeric nanoparticle formulation of curcumin (NanoCurc) significantly attenuates incidence of mammary tumors in a rodent chemical carcinogenesis model: implications for breast cancer chemoprevention in at-risk populations. Carcinogenesis. 2012;33:2242–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  288. Alfaro Y, Delgado G, Cárabez A, Anguiano B, Aceves C. Iodine and doxorubicin, a good combination for mammary cancer treatment: antineoplastic adjuvancy, chemoresistance inhibition, and cardioprotection. Mol Cancer. 2013;12:1–11.

    Article  CAS  Google Scholar 

  289. Kubatka P, Sadlonova V, Kajo K, Machalekova K, Ostatnikova D, Nosalova G, et al. Neoplastic effects of exemestane in premenopausal breast cancer model. Neoplasma. 2008;55:538–43.

    CAS  PubMed  Google Scholar 

  290. Gottardis M, Jordan C. Antitumor actions of keoxifene and tamoxifen in the N-nitrosomethylurea-induced rat mammary carcinoma model. Cancer Res. 1987;47:4020–4.

    CAS  PubMed  Google Scholar 

  291. Kubatka P, Sadlonova V, Kajo K, Nosalova G, Fetisovova Z. Preventive effects of letrozole in the model of premenopausal mammary carcinogenesis. Neoplasma. 2008;55:42–6.

    CAS  PubMed  Google Scholar 

  292. Garcia-Solis P, Yahia EM, Aceves C. Study of the effect of 'Ataulfo' mango (Mangifera indica L.) intake on mammary carcinogenesis and antioxidant capacity in plasma of N-methyl-N-nitrosourea (MNU)-treated rats. Food Chem. 2008;111:309–15.

    Article  CAS  PubMed  Google Scholar 

  293. Lippert TH, Adlercreutz H, Berger MR, Seeger H, Elger W, Mueck AO. Effect of 2-methoxyestradiol on the growth of methyl-nitroso-urea (MNU)-induced rat mammary carcinoma. J Steroid Biochem Mol Biol. 2003;84:51–6.

    Article  CAS  PubMed  Google Scholar 

  294. Okugawa H, Yamamoto D, Uemura Y, Sakaida N, Tanano A, Tanaka K, et al. Effect of perductal paclitaxel exposure on the development of MNU-induced mammary carcinoma in female S-D rats. Breast Cancer Res Treat. 2005;91:29–34.

    Article  CAS  PubMed  Google Scholar 

  295. Anzano MA, Peer CW, Smith JM, Mullen LT, Shrader MW, Logsdon DL, et al. Chemoprevention of mammary carcinogenesis in the rat: combined use of raloxifene and 9-cis-retinoic acid. J Natl Cancer Inst. 1996;88:123–5.

    Article  CAS  PubMed  Google Scholar 

  296. Sato M, Pei RJ, Yuri T, Danbara N, Nakane Y, Tsubura A. Prepubertal resveratrol exposure accelerates N-methyl-N-nitrosourea-induced mammary carcinoma in female Sprague-Dawley rats. Cancer Lett. 2003;202:137–45.

    Article  CAS  PubMed  Google Scholar 

  297. Martin G, Melito G, Rivera E, Levin E, Davio C, Cricco G, et al. Effect of tamoxifen on intraperitoneal N-nitroso-N-methylurea induced tumors. Cancer Lett. 1996;100:227–34.

    Article  CAS  PubMed  Google Scholar 

  298. Lubet RA, Christov K, Nunez NP, Hursting SD, Steele VE, Juliana MM, et al. Efficacy of Targretin on methylnitrosourea-induced mammary cancers: prevention and therapy dose-response curves and effects on proliferation and apoptosis. Carcinogenesis. 2005;26:441–8.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by Portuguese Foundation for Science and Technology (the research project PTDC/DES/114122/2009 and post-graduation grant to A.R.F. SFRH/BD/102099/2014).

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Authors and Affiliations

  1. Department of Veterinary Sciences, School of Agrarian and Veterinary Sciences, University of Trás-os-Montes and Alto Douro, UTAD, 5001-911, Vila Real, Portugal

    Ana I. Faustino-Rocha, Paula A. Oliveira, Adelina Gama & Mário Ginja

  2. Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), UTAD, 5001-911, Vila Real, Portugal

    Ana I. Faustino-Rocha, Paula A. Oliveira & Mário Ginja

  3. Organic Chemistry of Natural Products and Agrifood (QOPNA), Mass Spectrometry Center, Department of Chemistry, University of Aveiro, 3810-193, Aveiro, Portugal

    Rita Ferreira

  4. Animal and Veterinary Research Center (CECAV), School of Agrarian and Veterinary Sciences, UTAD, 5001-911, Vila Real, Portugal

    Adelina Gama

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  1. Ana I. Faustino-Rocha
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Faustino-Rocha, A.I., Ferreira, R., Oliveira, P.A. et al. N-Methyl-N-nitrosourea as a mammary carcinogenic agent. Tumor Biol. 36, 9095–9117 (2015). https://doi.org/10.1007/s13277-015-3973-2

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