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  • Title: Preferential mammary carcinogenic effects of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in human c-Ha-ras proto-oncogene transgenic rats.
    Author: Naito A, Suzuki A, Ueda S, Nomoto H, Toriyama-Baba H, Asamoto M, Tsuda H.
    Journal: Cancer Sci; 2004 May; 95(5):399-403. PubMed ID: 15132766.
    Abstract:
    In order to clarify the susceptibility of the Hras128 rat harboring copies of the human c-Ha-ras proto-oncogene to 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), Hras128 rats were intragastically treated with 100 mg/kg PhIP 8 times (females) or 80 mg/kg PhIP 10 times (males) over a 9-week period, then sacrificed at weeks 12 and 30. Multiple mammary tumors of adenocarcinoma type were induced in all females, while 83% of treated males developed adenocarcinomas, sarcomas and transitional carcinosarcomas, as evidenced by casein and vimentin immunoreactivity. All tumors examined had mutations in the c-Ha-ras transgene, while the endogenous rat c-Ha-ras gene was intact. Our results indicate that 1) Hras128 rats of both sexes are preferentially susceptible to mammary carcinogenesis with PhIP; 2) activation of the transgene, but not the endogenous c-Ha-ras gene, may be important in this regard; 3) the variety of tumor types evident in male rats indicates that immature mammary gland cells of the terminal end buds may be a target of PhIP; 4) although the transgene is expressed in all organs, susceptibility to PhIP is limited to mammary glands.
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