Summary
Among the multiple experimental animal models employed for analyzing the various aspects of mammary carcinogenesis, the induction of mammary tumors in rats by chemical carcinogens is one of the models most utilized. Experimentally-induced mammary tumors in rodents have proven to constitute useful tools for the study of the pathogenesis of cancer and of the molecular mechanisms involved in the initiation and progression of the neoplastic process. In vivo experimental animal models provide information not available in human populations; they are adequate for hazard identification, dose-response modeling, exposure assessment, and risk characterization, the four required steps for quantifying the estimated risk of cancer development associated with toxic chemical exposure. Using the DMBA rat mammary model, we have been able to demonstrate that the carcinogen acts on the intermediate cell of the terminal end bud (TEB), and that this structure is the one that evolves to intraductal proliferation, carcinoma in situ, and invasive carcinoma. There are several factors that regulate the susceptibility of the TEB; some of them are: a) topographic location of the mammary gland, b) age of the animal, and c) reproductive history. The understanding of the mechanisms that modulate tumorigenesis will further our knowledge and understanding in the prevention of the disease, as a result of the development of strategies for stopping the progression of the initiated cells.
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References
MacMahon B: Risk factors for endometrial cancer. Gynecol Oncol 2:122–128, 1974
MacMahon B, Cole P, Lin TM, et al: Age at first birth and breast cancer risk. Bull World Health Org 43:209–221, 1970
Russo J, Russo IH: Is differentiation the answer in breast cancer prevention? IRCS Med Sci 10:935–945, 1982
Russo J, Tay LK, Russo IH: Differentiation of the mammary gland and susceptibility to carcinogenesis. Breast Cancer Res Treat 2:5–73, 1982
McGregor DH, Land CE, Choi K, Tokuoka S, Liu PI, Wakabayashi I, Beebe GW: Breast cancer incidence among atomic bomb survivors, Hiroshima and Nagasaki 1950–1989. J Natl Cancer Inst 59:799–811, 1977
Russo J, Russo IH: Biological and molecular bases of mammary carcinogenesis. Lab Inv 57:112–137, 1987
Wellings SR: Development of human breast cancer. I. Advances in Cancer Research 31:287–299, 1980
Wellings SR, Jensen HM, Marcum RG: An atlas of subgross pathology of 16 human breasts with special reference to possible precancerous lesions. J Natl Cancer Inst 55:231–275, 1975
Dao TL: The role of ovarian hormones initiating the induction of mammary cancer in rats by polynuclear hydrocarbons. Cancer Res 22:973–980, 1962
Dao TL, Chan PC: Effect of duration of high fat intake on enhancement of mammary carcinogenesis in rats. J Natl Cancer Inst 71:201–208, 1983
Huggins C, Grand LC, Brillantes FP: Critical significance of breast structure in the induction of mammary cancer in the rat. Proc Natl Acad Sci USA 45:1294–1300, 1959
Huggins C, Yang NC: Induction and extinction of mammary cancer. Science 137:25–28, 1962
Ito N: Nitroquinolines.In: Sugimura T (ed) Carcinogenesis: A Comprehensive Survey, Vol. 6. Raven Press, New York, 1981, p 260
Russo IH, Russo J: Developmental stage of the rat mammary gland as determinant of its susceptibility to 7,12-dimethylbenz(a)anthracene. J Natl Cancer Inst 61:1439–1442, 1978
Russo J, Russo IH: DNA-labeling index and structure of the rat mammary gland as determinant of its susceptibility to carcinogenesis. J Natl Cancer Inst 61:1451–1459, 1978
Russo J, Russo IH: Pregnancy interruption as a risk factor in mammary carcinogenesis. Proc Am Assoc Cancer Res 21:2700, 1980
Russo J, Russo IH: Influence of differentiation and cell kinetics on the susceptibility of the rat mammary gland to carcinogenesis. Cancer Res 40:2677–2687, 1980
van Zwieten MJ: The rat as animal model in breast cancer research. Martinus Nijhoff Publishers, Boston, 1984
Young S, Hallowes RC: Tumours of the mammary gland.In: Turusov VS (ed) Pathology of Tumors in Laboratory Animals, Vol. 1, Tumours of the Rat. IARC Sci Publ 2:31, 1973
Rogers AE, Lee SY: Chemically-induced mammary gland tumors in rats: modulation by dietary fat.In: Ip C, Birt DF, Rogers AE, Mettlin C eds) Dietary Fat and Cancer. Alan R. Liss, New York, 1986, p 255
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 41:2690–2695, 1981
McCormick DL, Mehta RG, Thompson CA, Dinger N, Caldwell A, Moon RC: Enhanced inhibition of mammary carcinogenesis by combined treatment with N-(4-hydroxyphenyl) retinamide and ovariectomy. Cancer Res 42:508–512, 1982
Grubbs CJ, Juliana MM, Hill DL, Whitaker LM: Suppression by pregnancy of chemically induced preneoplastic cells of the rat mammary gland. Anticancer Res 6:2395–2401, 1986
Rose DP, Pruitt B, Stauber P, Erturk E, Bryan GT: Influence of dosage schedule on the biological characteristics of N-nitroso-N-methylurea-induced rat mammary tumors. Cancer Res 40:235–239, 1980
Chan PC, Dao TL: Effects of dietary fat on age-dependent sensitivity to mammary carcinogenesis. Cancer Letters 18:245–253, 1983
Russo J: Basis of cellular autonomy in susceptibility to carcinogenesis. Toxicol Pathol 11:149–166, 1983
Welsch CW: Host factors affecting the growth of carcinogen-induced rat mammary carcinomas: a review and tribute to Charles Brenton Huggins. Cancer Res 45:3415–3443, 1985
Thompson HJ, Ronan A: Effect of D,L-α-difluoromethylornithine and endocrine manipulation on the induction of mammary carcinogenesis by 1-methyl-1-nitrosourea. Carcinogenesis 57:2003–2009, 1987
Grubbs CJ, Farnell DR, Hill DL, McDonough KC: Chemoprevention of N-nitroso-N-methylurea-induced mammary cancers by pretreatment with 17β-estradiol and progesterone. J Natl Cancer Inst 4:927–932, 1985
Grubbs CJ, Hill DL, McDonough KC, Peckham JC: N-nitroso-N-methylurea-induced mammary carcinogenesis: effect of pregnancy in preneoplastic cells. J Natl Cancer Inst 71:625–628, 1983
Rothschild TC, Boylan ES, Calhoon RE, Vonderhaar BK: Transplacental effects of diethylstilbestrol on mammary development and tumorigenesis in female ACI rats. Cancer Res 47:4508–4516, 1987
Russo IH, Al-Rayess M, Russo J: Role of contraceptive agents in breast cancer prevention. Proc Biennial International Breast Cancer Research Conference, London, UK, March 24–28, 1985, p87
Russo IH, Al-Rayess M, Sabharwal S: Effect of contraceptive agents on mammary gland structure and susceptibility to carcinogenesis. Proc Am Assoc Cancer Res 26:460, 1985
Russo IH, Pokorzynski T, Russo J: Contraceptives as hormone preventative agents in mammary carcinogenesis. Proc Am Assoc Cancer Res 27:912, 1986
Lindsey WF, Das Gupta TK, Beattie CW: Influence of the estrous cycle during carcinogen exposure on nitrosomethylurea-induced rat mammary carcinoma. Cancer Res 41:3857–3862, 1981
Bakker GH, Setyono-Han B, Henkelman MS, de Jong FH, Lamberts SWJ, van der Schoot P, Klijn JGM: Comparison of the actions of the antiprogestin mifepristone (RU486), the progestin megestrol acetate, the LHRH analog buserelin, and ovariectomy in treatment of rat mammary tumors. Cancer Treatment Reports 71:1021–1027, 1987
Ratko TA, Beattie CW: Estrous cycle modification of rat mammary tumor induction by a single dose of N-methyl-N-nitrosourea. Cancer Res 45:3042–3047, 1985
Boylan ES, Calhoon RE: Transplacental action of diethylstilbestrol on mammary carcinogenesis in female rats given one or two doses of 7,12-dimethylbenz(a)anthracene. Cancer Res 43:4879–4884, 1983
Stone JP, Holtzman S, Shellabarger CJ: Neoplastic responses and correlated plasma prolactin levels in diethylstilbestrol-treated ACI and Sprague-Dawley rats. Cancer Res 39:773–778, 1979
Isaacs JT: Inheritance of a genetic factor from the Copenhagen rat and the suppression of chemically induced mammary adenocarcinogenesis. Cancer Res 48:2204–2213, 1988
Aylsworth CF, Cullum ME, Zile MH, Welsch CW: Influence of dietary retinyl acetate on normal rat mammary gland development and on the enhancement of 7,12-dimethylbenz(a)anthracene-induced rat mammary tumorigenesis by high levels of dietary fat. J Natl Cancer Inst 76:339–345, 1986
Clinton SK, Imrey PB, Alster JM, Simon J, Truex CR, Visek WJ: The combined effects of dietary protein and fat on 7,12-dimethylbenz(a)anthracene-induced breast cancer in rats. J Nutr 114:1213–1218, 1984
King MM, McCoy P, Russo IH: Dietary fat may influence DMBA initiated mammary gland carcinogenesis by modification of mammary gland development.In: Roe DA (ed) Current Topics in Nutrition and Disease. Alan R. Liss, New York, 1983, pp 61–90
Rogers AE, Conner B, Boulanger C, Lee S: Mammary tumorigenesis in rats fed diets high in lard. Lipids 21:275–284, 1986
Rogers AE, Conner BH, Boulanger C, Lee SY, Carr FA, Dumouchel WH: Enhancement of 7,12-dimethylbenz(a)anthracene mammary carcinogenesis by a high lard diet.In: Vahouny GV, Kritchevsky D (eds) Dietary Fiber. Plenum, 1985
Klurfeld DM, Weber MM, Kirtchevsky D: Inhibition of chemically induced mammary and colon tumor promotion by caloric restriction in rats fed increased dietary fat. Cancer Res 47:2759–2765, 1987
Kritchevsky D, Weber MM, Klurfeld DM: Dietary fat versus caloric content initiation and promotion of 7,12-dimethylbenz(a)anthracene-induced mammary tumorigenesis in rats. Cancer Res 44:3174–3177, 1984
Beth M, Berger MR, Aksoy M, Schmahl D: Comparison between the effects of dietary fat level and of calorie intake on methylnitrosourea-induced mammary carcinogenesis in female SD rats. Int J Cancer 39:737–744, 1987
Chan PC, Ferguson KA, Dao TL: Effects of different dietary fats on mammary carcinogenesis. Cancer Res 43:1079–1083, 1983
Cohen LA, Thompson DO, Maeura Y, Choi K, Blank ME, Rose DP: Dietary fat and mammary cancer. Promoting effects of different dietary fat on Nnitrosomethylurea-induced rat mammary tumorigenesis. J Natl Cancer Inst 77:33–42, 1986
Sylvester PW, Russell M, Ip MM, Ip C: Comparative effects on different animal and vegetable fats fed before and during carcinogen administration on mammary tumorigenesis, sexual maturation, and endocrine function in rats. Cancer Res 46:757–762, 1986
Wetsel WC, Rogers AE, Newberne PM: Dietary fat and DMBA mammary carcinogenesis in rats. Cancer Detection and Prevention 4:535–547, 1981
Clinton SK, Alster JM, Imrey PB, Nandkumar S, Truex CR, Visek WJ: Effects of dietary protein, fat and energy intake during an initiation phase study of 7,12-dimethylbenz(a)anthracene-induced breast cancer in rats. J Nutr 116:2290–2298, 1986
Lee SY, Walsh CT, Ng SF, Rogers AE: Toxicokinetics of 7,12-dimethylbenz(a)anthracene (DMBA) in rats fed high lard or control diets. J Nutr Growth and Cancer 3:167–173, 1986
Liotta LA, Rao CN, Barsky SH: Tumor invasion and the extracellular matrix. Lab Invest 49:636–649, 1983
Wetsel WC, Rutledge A, Rogers AE: Absence of an effect of dietary corn oil content on plasma prolactin, progesterone and 17β-estradiol in female Sprague-Dawley rats. Cancer Res 44:1420–1425, 1983
Lee SY, Ng SF, Busby WF, Rogers AE: Mammary gland DNA synthesis in rats fed high lard or control diets. J Nutr Growth and Cancer 4:167–173, 1988
Sylvester PW, Ip C, Ip M: Effects of high dietary fat on the growth and development of ovarian-independent carcinogen-induced mammary tumors in rats. Cancer Res 46:763–769, 1986
Benjamin H, Storkson J, Pariza MW: Effect of voluntary exercise of mammary tumor development. FASEB J 2:1191a, 1988
Thompson HJ, Ronan AM, Ritacco KA, Tagliaferro AR, Meeker LD: Effect of exercise on the induction of mammary carcinogenesis. Cancer Res 48:2720–2723, 1988
BEIR: Committee on the Biological Effects of Ionizing Radiations, National Research Council: Somatic effects: Cancer.In: The Effects on Populations of Exposure to Low Levels of Ionizing Radiation. National Academy of Sciences, Washington DC, 1980, chap 5, pp 135
Land CE, Boice JD, Shore RE, Norman JE, Tokunaga M: Breast cancer risk from low-dose exposures to ionizing radiation: results of parallel analysis of three exposed populations of women. J Natl Cancer Inst 65:353–376, 1980
Finerty JC, Binhammer RT, Schneider M, Cunningham AWB: Neoplasms in rats exposed to single-dose total-body X-radiation. J Natl Cancer Inst 14:149–154, 1953
Bond VP, Cronkite EP, Lippincott SW, Shellabarger CJ: Studies on radiation-induced mammary gland neoplasia in the rat. III. Relation of the neoplastic response to dose of total-body radiation. Radiat Res 12:276–284, 1960
Broerse JJ, Hennen LA, Solleveld HA: Actuarial analysis of the hazard for mammary carcinogenesis in different rat strains after X- and neutron irradiation. Leuk Res 10:749–754, 1986
van Bekkum DW, Broerse JJ, Hennen LA, Solleveld HA: The gene transfer-misrepair hypothesis of radiation carcinogenesis tested for induction of mammary tumors in rats. Leuk Res 10:761–765, 1986
Bond VP, Shellabarger CJ, Cronkite EP, Fliedner TM: Studies on radiation-induced mammary gland neoplasia in the rat. V. Induction by localized irradiation. Radiat Res 13:318–325, 1960
Shellabarger CJ: Pituitary and steroid hormones in radiation-induced mammary tumors.In: Pike MC, Siiteri PK, Welsch CW (eds) Hormones and Breast Cancer. Cold Spring Harbor Laboratory, 1981, p 339
Shellabarger CJ, Bond BP, Aponte GE, Cronkite EP: Results of fractionation and protraction of total-body radiation on rat mammary neoplasia. Cancer Res 26:509–513, 1966
Broerse JJ, Hennen LA, van Zwieten MJ, Hollander CF: Dose-effect relations for mammary carcinogenesis in different rat strains after irradiation with Xrays and monoenergetic neutrons. Biological Effects of Low-Level Radiation. IAEA, Vienna, 1983, p 507
Solleveld HA, van Zwieten MJ, Broerse JJ, Hollander CF: Effects of X-irradiation, ovariohysterectomy and estradiol-17β on incidence, benign/malignant ratio and multiplicity of rat mammary neoplasms — a preliminary report. Leuk Res 10:755–763,1986
Broerse JJ, Hennen LA, Klapwijk WM, Solleveld HA: Mammary carcinogenesis in different rat strains after irradiation and hormone administration. Int J Radiat Biol 51:1091–1099, 1987
Segaloff A, Maxfield WD: The synergism between radiation and estrogen in the production of mammary cancer in the rat. Cancer Res 31:166–168, 1971
Stone JP, Holtzman S, Shellabarger CJ: Synergistic interactions of various doses of diethylstilbestrol and X-irradiation on mammary neoplasia in female ACI rats. Cancer Res 40:3966–3972, 1980
Shellabarger CJ, Stone JP, Holtzman S: Rat differences in mammary tumor induction with estrogen and neutron radiation. J Natl Cancer Inst 61:1505–1508, 1978
Holtzman S, Stone JP, Shellabarger CJ: Influence of diethylstilbestrol treatment on prolactin cells of female ACI and Sprague-Dawley rats. Cancer Res 39:779–784, 1979
Yokoro K, Sumi C, Ito A, Hamada K, Kanda K, Kobayashi T: Mammary carcinogenic effect of lowdose fission radiation in Wistar/Furth rats and its dependency on prolactin. J Natl Cancer Inst 64:1459–1466, 1980
Blankenstein MA, Broerse JJ, van Zwieten MJ, van der Molen HJ: Prolactin concentration in plasma and susceptibility to mammary tumors in female rats from different strains treated chronically with estradiol-17β. Breast Cancer Res Treat 4:137–141, 1984
Holtzman S, Stone JP, Shellabarger CJ: Radiation-induced mammary carcinogenesis in virgin, pregnant, lactating and post-lactating rats. Cancer Res 42:50–53, 1982
Russo J, Russo IH: Biological and molecular bases of mammary carcinogenesis. Lab Invest 57:112–137, 1987
Russo J, Wilgus G, Russo IH: Susceptibility of the mammary gland to carcinogenesis. I. Differentiation of the mammary gland as determinant of tumor incidence and type of lesion. Am J Pathol 96:721–734, 1979
Russo J, Russo IH: DNA labeling index and structure of the rat mammary gland as determinants of its susceptibility to carcinogenesis. J Natl Cancer Inst 61:1451–1459, 1978
Russo J, Saby J, Isenberg W, Russo IH: Pathogenesis of mammary carcinomas induced in rats by 7,12-dimethylbenz(a)anthracene. J Natl Cancer Inst 59:435–445,1977
Russo J, Russo IH, van Zwieten MJ, Rogers AE, Gusterson B: Classification of neoplastic and non-neoplastic lesions of the rat mammary gland.In: Jones TC, Mohr U, Hunt RD (eds) Integument and Mammary Glands of Laboratory Animals. Springer Verlag, Berlin, 1989, pp 275–304
Russo J, Tay LK, Russo IH: Differentiation of the mammary gland and susceptibility to carcinogenesis: a review. Breast Cancer Res Treat 2:5–73, 1982
Russo IH, Tewari M, Russo J: Morphology and development of the rat mammary gland. In: Jones TC, Mohr U, Hunt RD (eds) Integument and Mammary Glands of Laboratory Animals. Springer Verlag, Berlin, 1989, pp 233–252
Russo IH, Russo J: Hormone prevention of mammary carcinogenesis: A new approach in anticancer research. Anticancer Res 8:1247–1264, 1988
Russo J, Russo IH, Ireland M, Saby J: Increased resistance of multiparous rat mammary gland to neoplastic transformation by 7,12-DMBA. Proc Am Assoc Cancer Res 18:140, 1977
Russo J, Miller J, Russo IH: Hormonal treatment prevents DMBA induced rat mammary carcinoma. Proc Am Assoc Cancer Res 23:348a, 1982
Russo J, Russo IH: Toward a biological approach to breast cancer prevention. Cancer Epidemiology, Biomarkers, and Prevention 3:353–364, 1994
Russo J, Russo IH: Susceptibility of the mammary gland to carcinogenesis II. Pregnancy interruption as a risk factor in tumor incidence. Am J Pathol 100:497–511, 1980
Tay LK, Russo J: Effect of human chorionic gonadotropin on 7,12-dimethylbenz(a)anthracene-induced DNA binding and repair synthesis by rat mammary epithelial cells. Chem-Biol Interact 55:13–21, 1985
Ciocca DR, Parente A, Russo J: Endocrinological milieu and susceptibility of the rat mammary gland to carcinogenesis. Am J Pathol 109:47–56, 1982
Russo J, Russo IH: Influence of differentiation and cell kinetics on the susceptibility of the rat mammary gland to carcinogenesis. Cancer Res 40:2677–2687 (1980)
Berenblum I: A speculative review: the probable nature of promoting action, its significance in the understanding of the mechanism of carcinogenesis. Cancer Res 14:471–476, 1976
Frei JV, Harsano T: Increased susceptibility to low doses of carcinogen of epidermal cells in stimulated DNA synthesis. Cancer Res 27:1482–1491, 1967
Kakunaga T: The role of cell division in the malignant transformation of mouse cells treated with 3-methylcholanthrene. Cancer Res 35:1637–1642, 1975
Marquardt H, Baker S, Tierney B, Grover PL, Sims P: Comparison of mutagenesis and malignant transformation by dihydrodiols of 7,12-dimethylbenz(a)anthracene. Br J Cancer 39:540–547, 1979
Tay LK, Russo J: 7,12-dimethylbenz(a)anthracene (DMBA) induced DNA binding and repair synthesis in susceptible and non-susceptible mammary epithelial cells in culture. J Natl Cancer Inst 67:155–161, 1981
Tay LK, Russo J: Formation and removal of 7,12-dimethylbenz(a)anthracene nucleic acid adducts in rat mammary epithelial cells with different susceptibility to carcinogenesis. Carcinogenesis 2:1327–1333, 1981
Hashimoto I, Tarnowski M, Lever WF: Reifung und Degranulierung der Mastzellen in der menschlichen Haut. Hautarzt 18:318–324, 1967
Dvorak HF, Dvorak AM: Basophils, mast cells and cellular immunity in animals and man. Human Pathol 3:454–456, 1972
Folkman J: How is blood vessel growth regulated in normal and neoplastic tissue? Cancer Res 46:467–473, 1986
Kessler DA, Langer RS, Pless NA, Folkman J: Mast cells and tumor angiogenesis. Int J Cancer 18:703–709, 1976
Gospodarowicz D, Cheng J, Lui GM, Baird A, Bohlent P: Isolation of brain fibroblast growth factor by heparin-sepharose affinity chromatography: identity with pituitary fibroblast growth factor. Proc Natl Acad Sci USA 81:6963–6967, 1984
Lobb RR, Fett JN: Purification of two distinct growth factors from bovine neural tissue by heparin affinity chromatography. Biochemistry 23:6295–6299, 1984
Lippman M: Transplantation and cytotoxicity changes induced by acid mucopolysaccharides. Nature 219:33–36, 1968
McBride WM, Bard JBL: Hyaluronidase-sensitive halos around adherent cells. J Exp Med 149:507–515, 1979
Ito I: Radioactive labeling of the surface coat on enteric microvilli. Anat Res 151:489a, 1965
Bekesi JG, Winzler RJ: The metabolism of plasma glycoproteins: Studies on the incorporation of L-fucose-1-14C into tissue and serum in the normal rat. J Biol Chem 242:3873–3879, 1967
Bossmann HB, Hagopian A, Eylar EH: Cellular membranes: the biosynthesis of glycoprotein and glycolipids in the HeLa cell membranes. Arch Biochem Biophys 130:573–583, 1969
Esko JD, Rostand KS, Weinke JL: Tumor formation dependent on proteoglycan biosynthesis. Science 241:1092–1096, 1988
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Russo, J., Russo, I.H. Experimentally induced mammary tumors in rats. Breast Cancer Res Tr 39, 7–20 (1996). https://doi.org/10.1007/BF01806074
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DOI: https://doi.org/10.1007/BF01806074