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Rapid Emergence of Mammary Preneoplastic and Malignant Lesions in Human c-Ha-ras Proto-Oncogene Transgenic Rats: Possible Application for Screening of Chemopreventive Agents

Experimental Pathology and Chemotherapy Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan

Katsumi Fukamachi

Experimental Pathology and Chemotherapy Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan

Tetsuya Hamaguchi

Experimental Pathology and Chemotherapy Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan

Hiroyasu Toriyama-Baba

Experimental Pathology and Chemotherapy Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan

Hiroaki Kawaguchi

1st Department of Pathology, Faculty of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan

Masato Kusunoki

2nd Department of Surgery, School of Medicine, Mie University, 2-174 Edobashi, Tsu, Mie 514-8507, Japan

Hiroki Yoshida

1st Department of Pathology, Faculty of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan

Hiroyuki Tsuda

Experimental Pathology and Chemotherapy Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan

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.

Key Words: Breast cancer • chemoprevention • ductal hyperplasia • isoflavone • mammary gland • N-methyl-N-nitrosourea • ras • transgenic rat.

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				T. Ohnishi, K. Fukamachi, Y. Ohshima, X. Jiegou, S. Ueda, M. Iigo, N. Takasuka, A. Naito, K.-i. Fujita, Y. Matsuoka, et al. Possible Application of Human c-Ha-ras Proto-Oncogene Transgenic Rats in a Medium-Term Bioassay Model for Carcinogens Toxicol Pathol, April 1, 2007; 35(3): 436 - 443. [Abstract] [Full Text] [PDF]