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‐me‐thyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP), Hras128 rats were in‐tragastically 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 adenocar‐cinoma type were induced in all females, while 83% of treated males developed adenocarcinomas, sarcomas and transitional car‐cinosarcomas, 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.