Skip to main content
Log in

Mammary tumorigenesis and chemoprevention studies in carcinogen-treated rats

  • Published:
Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

The objectives of this review are to describe the induction of mammary gland tumors by chemical carcinogens and to discuss their application to mammary cancer chemoprevention research. Special emphasis will be placed on the dimethylbenz[a]anthracene (DMBA) and methylnitrosourea (MNU) models because of the extensive information available about the pathogenesis of tumor growth associated with these two compounds. Both models have been widely used in the investigation of novel cancer chemopreventive agents. The current status of a number of different approaches will be summarized briefly here to provide an overview of research opportunities. Despite the popularity of the DMBA and MNU models in laboratory studies of mammary cancer biology and prevention, neither of these carcinogens has ever been implicated in the etiology of human breast cancer. This shortcoming has prompted a growing interest in other relevant environmental chemicals which are capable of producing mammary tumors in experimental animals. The new models have yet to be fully characterized, but they may be more appropriate than the DMBA and MNU models as paradigms for assessing cancer risk in humans and for developing suitable cancer prevention strategies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. C. W. Welsch (1985). Host factors affecting the growth of carcinogen-induced rat mammary carcinomas: A review and tribute to Charles Brenton Huggins.Cancer Res. 453415–3443.

    PubMed  Google Scholar 

  2. W. F. Dunning, M. R. Curtis, and F. D. Bullock (1936). The respective roles of heredity and somatic mutation in the origin of malignancy.Am. J. Cancer 28681–712.

    Google Scholar 

  3. C. F. Geschickter (1939). Estrogenic mammary cancer in the rat.Radiology 33439–449.

    Google Scholar 

  4. R. P. Geyer, V. R. Bleisch, J. E. Bryant, A. N. Robbins, I. M. Saslaw, and F. J. Stare (1951). Tumor production in rats injected intravenously with oil emulsions containing 9,10-dimethyl-1,2-benzanthracene.Cancer Res. 11474–478.

    PubMed  Google Scholar 

  5. C. Huggins, L. C. Grand, and F. P. Brillantes (1961). Mammary cancer induced by a single feeding of polynuclear hydrocarbons and its suppression.Nature 189204–207.

    PubMed  Google Scholar 

  6. D. Sinha and T. L. Dao (1974). A direct mechanism of mammary carcinogenesis induced by 7,12-dimethylbenz[a]anthracene.J. Natl. Cancer Inst. 53841–846.

    PubMed  Google Scholar 

  7. J. T. Issacs (1986). Genetic control of resistance to chemically-induced mammary adenocarcinogenesis in the rat.Cancer Res. 463958–3963.

    PubMed  Google Scholar 

  8. T. L. Dao (1969). Mammary cancer induction by 7,12-dimethylbenz(a)anthracene: Relation to age.Science 165810–811.

    PubMed  Google Scholar 

  9. D. K. Sinha, J. E. Pazik, and T. L. Dao (1983). Progression of rat mammary development with age and its relationship to carcinogenesis by a chemical carcinogen.Int. J. Cancer 31321–327.

    PubMed  Google Scholar 

  10. P. J. Middleton (1965). The histogenesis of mammary tumours induced in the rat by chemical carcinogens.Br. J. Cancer 19830–839.

    PubMed  Google Scholar 

  11. L. J. Beuving, L. J. Faulkin, K. B. DeOme, and V. V. Bergs (1967). Hyperplastic lesions in the mammary glands of Sprague-Dawley rats after 7,12-dimethylbenz[a]anthracene treatment.J. Natl. Cancer Inst. 39423–429.

    PubMed  Google Scholar 

  12. L. J. Beuving (1968). Mammary tumor formation within outgrowths of transplanted hyperplastic nodules from carcinogen-treated rats.J. Natl. Cancer Inst. 401287–1289.

    PubMed  Google Scholar 

  13. D. Sinha and T. L. Dao (1975). Brief communication: Site of origin of mammary tumors induced by 7,12-dimethylbenz[a]anthracene in the rat.J. Natl. Cancer Inst. 541007–1009.

    PubMed  Google Scholar 

  14. J. Russo, J. Saby, W. M. Isenberg, and I. H. Russo (1977). Pathogenesis of mammary carcinomas induced in rats by 7,12-dimethylbenz[a]anthracene.J. Natl. Cancer Inst. 59435–445.

    Google Scholar 

  15. S. Z. Haslam (1980). The effect of age on the histopathogenesis of 7,12-dimethylbenz(a)anthracene-induced mammary tumors in the Lewis rat.Int. J. Cancer 26349–356.

    PubMed  Google Scholar 

  16. L. J. Beuving (1969). Effects of ovariectomy on preneoplastic nodule formation and maintenance in the mammary glands of carcinogen-treated rats.J. Natl. Cancer Inst. 431181–1189.

    PubMed  Google Scholar 

  17. J. Russo, L. K. Tay, and I. H. Russo (1982). Differentiation of the mammary gland and susceptibility to carcinogenesis.Breast Cancer Res. Treat. 25–73.

    Article  PubMed  Google Scholar 

  18. J. Russo and I. H. Russo (1991). Boundaries in mammary carcinogenesis. In O. Sudilovskyet al. (eds.),Boundaries between Promotion and Progression during Carcinogenesis, Plenum Press, New York, pp. 43–59.

    Google Scholar 

  19. P. M. Gullino, H. M. Pettigrew, and F. H. Grantham (1975).N-Nitrosomethylurea as mammary gland carcinogen in rats.J. Natl. Cancer Inst. 54401–414.

    PubMed  Google Scholar 

  20. G. T. A. M. Bots and R. G. J. Willighagen (1975). Tumours in the mammary gland induced in Lewis rats by intravenous methylnitrosourea.Br. J. Cancer 31372–274.

    PubMed  Google Scholar 

  21. D. P. Rose, B. Pruitt, P. Stauber, E. Ertürk, and G. T. Bryan (1980). Influence of dosage schedule on the biological characteristics ofN-nitrosomethylurea-induced rat mammary tumors.Cancer Res. 40235–239.

    PubMed  Google Scholar 

  22. J. C. William, B. Gusterson, J. Humphreys, P. Monaghan, R. C. Coombes, P. Rudland, and A. M. Neville (1981).N-Methyl-N-nitrosourea-induced rat mammary tumors. Hormone responsiveness but lack of spontaneous metastasis.J. Natl. Cancer Inst. 66147–155.

    PubMed  Google Scholar 

  23. D. L. McCormick, C. B. Adamowski, A. Fiks, and R. C. Moon (1981). Lifetime dose-response relationships for mammary tumor induction by a single administration ofN-methyl-N-nitrosourea.Cancer Res. 411690–1694.

    PubMed  Google Scholar 

  24. H. J. Thompson and H. Adlakha (1991). Dose-responsive induction of mammary gland carcinomas by the intraperitoneal injection of 1-methyl-1-nitrosourea.Cancer Res. 513411–3415.

    PubMed  Google Scholar 

  25. C. J. Grubbs, J. C. Peckham, and K. D. Cato (1983). Mammary carcinogenesis in rats in relation to age at time ofN-nitroso-N-methylurea administration.J. Natl. Cancer Inst. 70209–212.

    PubMed  Google Scholar 

  26. H. J. Thompson, H. Adlakha, and M. Singh (1992). Effect of carcinogen dose and age at administration on induction of mammary carcinogenesis by 1-methyl-1-nitrosourea.Carcinogenesis 131535–1539.

    PubMed  Google Scholar 

  27. L. W. Wattenberg (1992). Inhibition of carcinogenesis by minor dietary constituents.Cancer Res. 522085s-2091s.

    PubMed  Google Scholar 

  28. K. El-Bayoumy (1994). Evaluation of chemopreventive agents against breast cancer and proposed strategies for future clinical intervention trials.Carcinogenesis 152395–2420.

    PubMed  Google Scholar 

  29. F. B. Daniel and N. J. Joyce (1983). DNA adduct formation by 7,12-dimethylbenz[a]anthracene and its noncarcinogenic 2-fluoro analogue in female Sprague-Dawley rats.J. Natl. Cancer Inst. 70111–118.

    PubMed  Google Scholar 

  30. K. W. Singletary and J. A. Milner (1986). DNA binding and adduct formation of 7,12-dimethylbenz[a]anthracene by rat mammary epithelial cell aggregatesin vitro.Carcinogenesis 795–98.

    PubMed  Google Scholar 

  31. J. Liu, K. Gilbert, H. M. Parker, W. M. Haschek, and J. A. Milner (1991). Inhibition of 7,12-dimethylbenz(a)anthracene-induced mammary tumors and DNA adducts by dietary selenite.Cancer Res. 514613–4617.

    PubMed  Google Scholar 

  32. K. El-Bayoumy, Y.-H. Chae, P. Upadhyaya, C. Meschter, L. A. Cohen, and B. S. Reddy (1992). Inhibition of 7,12-dimethylbenz(a)anthracene-induced tumors and DNA adduct formation in the mammary glands of female Sprague-Dawley rats by the synthetic organoselenium compound, 1,4-phenylenebis(methylene)selenocyanate.Cancer Res. 522402–2407.

    PubMed  Google Scholar 

  33. C. Ip, S. Vadhanavikit, and H. Ganther (1995). Cancer chemoprevention by aliphatic selenocyanates: Effect of chain length on inhibition of mammary tumors and DMBA adducts.Carcinogenesis 1635–38.

    PubMed  Google Scholar 

  34. F. P. Guengerich (1991). Oxidation of toxic and carcinogenic chemicals by human cytochrome P-450 enzymes.Chem. Res. Toxicol. 4391–407.

    Article  PubMed  Google Scholar 

  35. C. S. Yang, T. J. Smith, and J.-Y. Hong (1994). Cytochrome P-450 enzymes as targets for chemoprevention against chemical carcinogenesis and toxicity: Opportunities and limitations.Cancer Res. 541982s-1986s.

    PubMed  Google Scholar 

  36. P. Talalay (1989). Mechanisms of induction of enzymes that protect against chemical carcinogenesis.Adv. Enzyme Regul. 28237–250.

    Article  PubMed  Google Scholar 

  37. Y. Zhang, P. Talalay, C.-G. Cho, and G. H. Posner (1992). A major inducer of anticarcinogenic protective enzymes from broccoli: Isolation and elucidation of structure.Proc. Natl. Acad. Sci. USA 892399–2403.

    PubMed  Google Scholar 

  38. Y. Zhang, T. W. Kensler, C.-G. Cho, G. H. Posner, and P. Talalay (1994). Anticarcinogenic activities of sulforaphane and structurally related synthetic norbornyl isothiocyanates.Proc. Natl. Acad. Sci. USA 913147–3150.

    PubMed  Google Scholar 

  39. K. K. Richardson, F. C. Richardson, R. M. Crosby, J. A. Swenberg, and T. R. Skopek (1987). DNA base changes and alkylation followingin vivo exposure ofEscherichia coli toN-methyl-N-nitrosourea orN-ethyl-N-nitrosourea.Proc. Natl. Acad. Sci. USA 84344–378.

    PubMed  Google Scholar 

  40. S. Sukumar, V. Notario, D. Martin-Zanca, and M. Barbacid (1983). Induction of mammary carcinomas in rats by nitrosomethylurea involves malignant activation of Ha-ras-1 locus by single point mutations.Nature 306658–661.

    Article  PubMed  Google Scholar 

  41. H. Zarbl, S. Sukumar, A. V. Arthur, D. Martin-Zanca, and M. Barbacid (1985). Direct mutagenesis of Ha-ras-1 oncogenes byN-nitroso-N-methylurea during initiation of mammary carcinogenesis in rats.Nature 315382–385.

    Article  PubMed  Google Scholar 

  42. S.-J. Lu and M. C. Archer (1992). Ha-ras oncogene activation in mammary glands ofN-methyl-N-nitrosourea-treated rats genetically resistant to mammary adenocarcinogenesis.Proc. Natl. Acad. Sci. USA 891001–1005.

    PubMed  Google Scholar 

  43. A. E. Pegg (1988). Polyamine metabolism and its importance in neoplastic growth and as a target for chemotherapy.Cancer Res. 48759–774.

    PubMed  Google Scholar 

  44. H. J. Thompson, E. J. Herbst, L. D. Meeker, R. Minocha, A. M. Ronan, and R. Fite (1984). Effect of D,L-α-difluoromethylornithine on murine mammary carcinogenesis.Carcinogenesis 51649–1651.

    PubMed  Google Scholar 

  45. C. Ip and H. Thompson (1989). New approaches to cancer chemoprevention with difluoromethylornithine and selenite.J. Natl. Cancer Inst. 81839–843.

    PubMed  Google Scholar 

  46. C. A. Carter, M. M. Ip, and C. Ip (1989). A comparison of the effects of the prostaglandin synthesis inhibitors indomethacin and carprofen on 7,12-dimethylbenz[a]anthracene-induced mammary tumorigenesis in rats fed different amounts of essential fatty acid.Carcinogenesis 101369–1374.

    PubMed  Google Scholar 

  47. M. Noguchi, T. Taniya, N. Koyasaki, T. Kumaki, I. Miyazaki, and Y. Mizukami (1991). Effects of prostaglandin synthetase inhibitor indomethacin on tumorigenesis, tumor proliferation, cell kinetics, and receptor contents of 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in Sprague-Dawley rats fed a high- or low-fat diet.Cancer Res. 512683–2689.

    PubMed  Google Scholar 

  48. C. W. Boone, G. J. Kelloff, and W. E. Malone (1990). Identification of candidate cancer chemopreventive agents and their evaluation in animal models and human clinical trials: A review.Cancer Res. 502–9.

    PubMed  Google Scholar 

  49. D. L. Earnest, L. J. Hixson, and D. S. Alberts (1992). Piroxicam and other cyclooxygenase inhibitors: Potential for cancer chemoprevention.J. Cell. Biochem. 161156–166.

    Article  Google Scholar 

  50. W. A. Maltese, K. M. Sheridan, E. M. Repko, and R. A. Erdman (1990). Post-translational modification of low molecular mass GTP-binding proteins by isoprenoid.J. Biol. Chem. 2652148–2155.

    PubMed  Google Scholar 

  51. K. Kato, A. D. Cox, M. M. Hisaka, S. M. Graham, J. E. Buss, and C. J. Der (1992). Isoprenoid addition toras protein is the critical modification for its membrane association and transforming activity.Proc. Natl. Acad. Sci. USA 896403–6407.

    PubMed  Google Scholar 

  52. J. A. Elegbede, C. E. Elson, A. Qureshi, M. A. Tanner, and M. N. Gould (1984). Inhibition of DMBA-induced mammary cancer by the monoterpene d-limonene.Carcinogenesis 5661–664.

    PubMed  Google Scholar 

  53. T. H. Maltzman, L. H. Hurt, C. E. Elson, M. A. Tanner, and M. N. Gould (1989). The prevention of nitrosomethylurea-induced mammary tumors by d-limonene and orange oil.Carcinogenesis 10781–783.

    PubMed  Google Scholar 

  54. J. D. Haag, M. J. Lindstrom, and M. N. Gould (1992). Limonene-induced regression of mammary carcinomas.Cancer Res. 524021–4026.

    PubMed  Google Scholar 

  55. P. L. Crowell, R. R. Chang, Z. Ren, C. E. Elson, and M. N. Gould (1991). Selective inhibition of isoprenylation of 21–26 kDa proteins by the anticarcinogen d-limonene and its metabolites.J. Biol. Chem. 26617679–17685.

    PubMed  Google Scholar 

  56. R. Lotan (1993). Squamous cell differentiation markers in normal, premalignant, and malignant epithelium: Effects of retinoids.J. Cell. Biochem. 17F167–174.

    Article  Google Scholar 

  57. R. C. Moon and R. G. Mehta (1990). Cancer chemoprevention by retinoids: Animal models.Meth. Enzymol. 190395–406.

    PubMed  Google Scholar 

  58. D. L. McCormick, R. G. Mehta, C. A. Thompson, N. Dinger, J. A. Caldwell, and R. C. Moon (1982). Enhanced inhibition of mammary carcinogenesis by combined treatment withN-(4-hydroxyphenyl)retinamide and ovariectomy.Cancer Res. 42508–512.

    PubMed  Google Scholar 

  59. J. A. Fontana, C. Nervi, Z.-M. Shao, and A. M. Jetten (1992). Retinoid antagonism of estrogen-responsive transforming growth factor α andpS2 gene expression in breast carcinoma cells.Cancer Res. 523938–3945.

    PubMed  Google Scholar 

  60. M. M. Gottardis and V. C. Jordan (1987). Antitumor actions of keoxifene and tamoxifen in theN-nitrosomethylurea-induced rat mammary carcinoma model.Cancer Res. 474020–4024.

    PubMed  Google Scholar 

  61. R. A. Lubet, V. E. Steele, T. L. Casebolt, I. Eto, G. J. Kelloff, and C. J. Grubbs (1994). Chemopreventive effects of the aromatase inhibitors vorozole (R-83842) and 4-hydroxyandrostenedione in the methylnitrosourea (MNU)-induced mammary tumor model in Sprague-Dawley rats.Carcinogenesis 152775–2780.

    PubMed  Google Scholar 

  62. R. K. Tiwari, L. Guo, H. L. Bradlow, N. T. Telang, and M. P. Osborne (1994). Selective responsiveness of human breast cancer cells to indole-3-carbinol, a chemopreventive agent.J. Natl. Cancer Inst. 86126–131.

    PubMed  Google Scholar 

  63. C. J. Grubbs, D. R. Farnell, D. L. Hill, and K. C. McDonough (1985). Chemoprevention ofN-nitroso-N-methylurea-induced mammary cancers by pretreatment with 17-estradiol and progesterone.J. Natl. Cancer Inst. 74927–931.

    PubMed  Google Scholar 

  64. I. H. Russo, M. Koszalka, and J. Russo (1990). Effect of human chorionic gonadotropin on mammary gland differentiation and carcinogenesis.Carcinogenesis 111849–1855.

    PubMed  Google Scholar 

  65. C. J. Grubbs, M. M. Juliana, D. L. Hill, and L. M. Whitaker (1986). Suppression by pregnancy of chemically induced prenoeplastic cells of the rat mammary gland.Anticancer Res. 61395–1400.

    PubMed  Google Scholar 

  66. D. K. Sinha, J. E. Pazik, and T. L. Dao (1988). Prevention of mammary carcinogenesis in rats by pregnancy: Effect of full-term and interrupted pregnancy.Br. J. Cancer 57390–394.

    PubMed  Google Scholar 

  67. K. El-Bayoumy (1992). Environmental carcinogens that may be involved in human breast cancer etiology.Chem. Res. Toxicol. 5585–590.

    Article  PubMed  Google Scholar 

  68. E. L. Cavaliere, S. Higginbotham, N. V. S. Ramakrishna, P. D. Devanensan, R. Todorovic, E. G. Rogan, and S. Salmasi (1991). Comparative dose-response tumorigenicity studies of dibenzo[a,l]pyrene versus 7,12-dimethylbenz[a]anthracene, benzo[a]pyrene and two dibenzo[a,l]pyrene dihydrodiols in mouse skin and rat mammary gland.Carcinogenesis 121939–1944.

    PubMed  Google Scholar 

  69. D. L. McCormick, F. J. Burns, and R. E. Albert (1981). Inhibition of benzo[a]pyrene-induced mammary carcinogenesis by retinyl acetate.J. Natl. Cancer Inst. 66559–564.

    PubMed  Google Scholar 

  70. E. G. Snyderwine (1994). Some perspectives on the nutritional aspects of breast cancer research. Food-derived heterocyclic amines as etiologic agents in human mammary cancer.Cancer 741070–1077.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ip, C. Mammary tumorigenesis and chemoprevention studies in carcinogen-treated rats. J Mammary Gland Biol Neoplasia 1, 37–47 (1996). https://doi.org/10.1007/BF02096301

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02096301

Key words

Navigation