Rapid Emergence of Mammary Preneoplastic and Malignant Lesions in Human c-Ha-ras Proto-Oncogene Transgenic Rats: Possible Application for Screening of Chemopreventive Agents
Free accessResearch articleFirst published online October, 2003
Rapid Emergence of Mammary Preneoplastic and Malignant Lesions in Human c-Ha-ras Proto-Oncogene Transgenic Rats: Possible Application for Screening of Chemopreventive Agents
For comparison of mammary gland whole mounts with examination of 2 histologic sections of mammary gland, 56 Hras128 rats were intravenously injected with 50 mg/kg body weight of N-methyl-N-nitrosourea at 50 days of age and then sacrificed at days 5, 10, 15, 20, 25, and 56. Comparison of detection sensitivity between the whole mounts and histologic sections revealed no lesions apparent in whole mounts on day 10, although intraductal proliferation was clearly detected in histologic sections in 44% of treated rats. Proliferative lesions were first detected in whole mounts at a 44% incidence on day 15, while intraductal proliferations and atypical hyperplasias were apparent in the sections at 89% and 44% incidences, respectively. On day 20, atypical hyperplasias and small adenocarcinomas in histologic sections were found in almost all animals. In conclusion, examination of 2 histologic sections from mammary tissues was found to be practical for detection of small malignant lesions as early as 15 days after MNU injection, and suppressive effects of soy isoflavones were clearly evident within 20 days after carcinogen exposure. These results suggest that this model has practical utility for short-term screening of chemopreventive agents for mammary carcinogenesis.
Ando K., Saitoh A., Hino O., Takahashi R., Kimura M., Katsuki M. (1992). Chemically induced forestomach papillomas in transgenic mice carry mutant human c-Ha-ras transgenes. Cancer Res52: 978—982.
2.
Asamoto M., Ochiya T., Toriyama-Baba H., Ota T., Sekiya T., Terada M., Tsuda H. (2000). Transgenic rats carrying human c-Ha-ras proto-oncogenes are highly susceptible to N-methyl-N-nitrosourea mammary carcinogenesis. Carcinogenesis21: 243—249.
3.
Asamoto M., Toriyama-Baba H., Ohnishi T., Naito A., Ota T., Ando A., Ochiya T., Tsuda H. (2002). Transgenic rats carrying human c-Ha-ras proto-oncogene are highly susceptible to N-Nitrosomethylbenzylamine induction of esophageal tumorigenesis. Jpn J Cancer Res93: 744—751.
4.
Barnes S., Peterson TG (1995). Biochemical targets of the isoflavone genistein in tumor cell lines. Proc Soc Exp Biol Med208: 103—108.
5.
Constantinou A., Huberman E. (1995). Genistein as an inducer of tumor cell differentiation: possible mechanisms of action. Proc Soc Exp Biol Med208: 109—115.
6.
de Camargo JL , Tsuda H., Asamoto M., Tagawa Y., Wada S., Nagase S., Ito N. (1993). Modifying effects of chemicals on the development of liver preneoplastic placental glutathione S-transferase positive foci in analbuminemic and Sprague-Dawley rats. Toxicol Pathol21: 409—416.
7.
Dragan Y., Valdes R., Gomez-Angelats M., Felipe A., Javier Casado F, Pitot H., Pastor-Anglada M. (2000). Selective loss of nucleoside carrier expression in rat hepatocarcinomas. Hepatology32: 239—246.
8.
Fotsis T., Pepper M., Adlercreutz H., Fleischmann G., Hase T., Montesano R., Schweigerer L. (1993). Genistein, a dietary-derived inhibitor of in vitro angiogenesis. Proc Natl Acad Sci USA90: 2690—2694.
9.
Fotsis T., Pepper MS, Aktas E., Breit S., Rasku S., Adlercreutz H., Wahala K., Montesano R., Schweigerer L. (1997). Flavonoids, dietary-derived inhibitors of cell proliferation and in vitro angiogenesis. Cancer Res57: 2916—2921.
10.
French J., Storer RD, Donehower LA (2001). The nature of the heterozygous Trp53 knockout model for identification of mutagenic carcinogens. Toxicol Pathol29(Suppl): 24—29.
11.
Han BS, Fukamachi K., Takasuka N., Ohnishi T., Maeda M., Yamasaki T., Tsuda H. (2002). Inhibitory effects of 17-beta-estradiol and 4-n-octylphenol on 7,12-dimethylbenz[a]anthracene-induced mammary tumor development in human c-Ha-ras proto-oncogene transgenic rats. Carcinogenesis23: 1209—1215.
12.
Hully JR, Su Y., Lohse JK, Griep AE, Sattler CA, Haas MJ, Dragan Y., Peterson J., Neveu M., Pitot HC (1994). Transgenic hepatocarcinogenesis in the rat. Am J Pathol145: 386—397.
13.
Lamartiniere CA, Moore J., Holland M., Barnes S. (1995). Neonatal genistein chemoprevents mammary cancer. Proc Soc Exp Biol Med208: 120—123.
14.
Messina MJ, Persky V., Setchell KD, Barnes S. (1994). Soy intake and cancer risk: a review of the in vitro and in vivo data. Nutr Cancer21: 113—131.
15.
Ota T., Asamoto M., Toriyama-Baba H., Yamamoto F., Matsuoka Y., Ochiya T., Sekiya T., Terada M., Akaza H., Tsuda H. (2000). Transgenic rats carrying copies of the human c-Ha-ras proto-oncogene exhibit enhanced susceptibility to N-butyl-N-(4-hydroxybutyl)nitrosamine bladder carcinogenesis. Carcinogenesis21: 1391—1396.
16.
Ozaki K., Sukata T., Yamamoto S., Uwagawa S., Seki T., Kawasaki H., Yoshitake A., Wanibuchi H., Koide A., Mori Y., Fukushima S. (1998). High susceptibility of p53(+/-) knockout mice in N-butyl-N-(4-hydroxybutyl)nitrosamine urinary bladder carcinogenesis and lack of frequent mutation in residual allele. Cancer Res58: 3806—3811.
17.
Page DL, Dupont WD (1993). Anatomic indicators (histologic and cytologic) of increased breast cancer risk. Breast Cancer Res Treat28: 157—166.
18.
Parker SL, Tong T., Bolden S., Wingo PA (1996). Cancer statistics, 1996. CA Cancer J Clin46: 5—27.
19.
Russo J., Wilgus G., Russo IH (1979). Susceptibility of the mammary gland to carcinogenesis: I Differentiation of the mammary gland as determinant of tumor incidence and type of lesion. Am J Pathol96: 721—736.
20.
Russo J., Russo IH (1987). Biological and molecular bases of mammary carcinogenesis . Lab Invest57: 112—137.
21.
Russo J., Gusterson BA, Rogers AE, Russo IH, Wellings SR, van Zwieten MJ (1990). Comparative study of human and rat mammary tumorigenesis . Lab Invest62: 244—278.
22.
Russo J., Russo IH (1996). Experimentally induced mammary tumors in rats . Breast Cancer Res Treat39: 7—20.
23.
Sato Y., Mukai K., Furuya S., Kameya T., Hirohashi S. (1992). The AMeX method: a multipurpose tissue-processing and paraffin-embedding method. Extraction of protein and application to immunoblotting . Am J Pathol140: 775—779.
24.
Shao ZM, Alpaugh ML, Fontana JA, Barsky SH (1998). Genistein inhibits proliferation similarly in estrogen receptor-positive and negative human breast carcinoma cell lines characterized by P21WAF1/CIP1 induction, G2/M arrest, and apoptosis. J Cell Biochem69: 44—54.
25.
Shao ZM, Wu J., Shen ZZ, Barsky SH (1998). Genistein exerts multiple suppressive effects on human breast carcinoma cells. Cancer Res58: 4851— 4857.
26.
Singh M., McGinley JN, Thompson HJ (2000). A comparison of the histopathology of premalignant and malignant mammary gland lesions induced in sexually immature rats with those occurring in the human. Lab Invest80: 221—231.
27.
Storer RD, Cartwright ME, Cook WO, Soper KA, Nichols, WW (1995). Short-term carcinogenesis bioassay of genotoxic procarcinogens in PIM transgenic mice. Carcinogenesis16: 285—293.
28.
Sukumar S., McKenzie K., Chen Y. ( 1995). Animal models for breast cancer. Mutat Res333: 37—44.
29.
Tennant RW, Spalding J., French JE (1996). Evaluation of transgenic mouse bioassays for identifying carcinogens and noncarcinogens. Mutat Res365: 119—127.
30.
Tennant RW, Stasiewicz S., Mennear J., French JE, Spalding JW (1999). Genetically altered mouse models for identifying carcinogens. IARC Sci Publ123—150.
31.
Thompson HJ , Adlakha H. (1991). Dose-responsive induction of mammary gland carcinomas by the intraperitoneal injection of 1-methyl-1-nitrosourea . Cancer Res51: 3411—3415.
32.
Thompson HJ , Adlakha H., Singh M. (1992). Effect of carcinogen dose and age at administration on induction of mammary carcinogenesis by 1-methyl-1-nitrosourea . Carcinogenesis13: 1535—1539.
33.
Thompson HJ , McGinley JN, Rothhammer K., Singh M. (1995). 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. Carcinogenesis16: 2407—2411.
34.
Thompson HJ , McGinley JN, Wolfe P., Singh M., Steele VE, Kelloff GJ (1998). Temporal sequence of mammary intraductal proliferations, ductal carcinomas in situ and adenocarcinomas induced by 1-methyl-1-nitrosourea in rats. Carcinogenesis19: 2181—2185.
35.
Thorgeirsson SS, Factor VM, Snyderwine EG (2000). Transgenic mouse models in carcinogenesis research and testing. Toxicol Lett112—113: 553— 555.
36.
Tsuda H., Asamoto M., Ochiya T., Toriyama-Baba H., Naito A., Ota T., Sekiya T., Terada M. (2001). High susceptibility of transgenic rats carrying the human c-Ha-ras proto-oncogene to chemically-induced mammary carcinogenesis . Mutat Res477: 173—182.
37.
Yamamoto S. , Mitsumori K., Kodama Y., Matsunuma N., Manabe S., Okamiya H., Suzuki H., Fukuda T., Sakamaki Y., Sunaga M., Nomura G., Hioki K., Wakana S., Nomura T., Hayashi Y. (1996). Rapid induction of more malignant tumors by various genotoxic carcinogens in transgenic mice harboring a human prototype c-Ha-ras gene than in control non-transgenic mice. Carcinogenesis17: 2455—2461.
