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.
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.
Naito
Akihiro
A
Experimental Pathology and Chemotherapy Division, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.
Suzuki
Akane
A
Ueda
Shinobu
S
Nomoto
Hiroshi
H
Toriyama-Baba
Hiroyasu
H
Asamoto
Makoto
M
Tsuda
Hiroyuki
H
D000818:Animals; D030801:Animals, Genetically Modified; D002273:Carcinogens / Q000633:toxicity*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D004273:DNA, Neoplasm / Q000032:analysis; D015536:Down-Regulation; D005260:Female; D011905:Genes, ras / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D007093:Imidazoles / Q000633:toxicity*; D008321:Mammary Glands, Animal / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000139:chemically induced*; D016133:Polymerase Chain Reaction; D000090063:Proto-Oncogene Mas; D051381:Rats
D002273:Carcinogens; D004273:DNA, Neoplasm; D007093:Imidazoles; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine