Chemical effects in transgenic mice bearing oncogenes expressed in mammary tissue.

Three transgenic mouse lines carrying v-Ha-ras (TG-SH), c-myc (TG-M) or c-neu (TG-NK) oncogenes under regulatory control of mouse mammary tumor virus (MMTV) long terminal repeat (LTR) sequences were evaluated for responses to two chemical carcinogens. p-Cresidine, a mutagenic urinary bladder carcinogen, increased the incidence of urinary bladder carcinomas in males and females in all three lines, and these tumors occurred at comparable incidences and grade in transgenic and non-transgenic mice. p-Cresidine did not affect the rates of mammary or salivary gland neoplasms in transgenic mice; these tumors did not occur in non-transgenic littermates. No other tumor types were observed in exposed or control animals. Reserpine, a non-mutagenic mammary gland carcinogen, was administered under the same protocol, but the high control rates of mammary gland adenocarcinomas in the TG-M and TG-NK strains made it difficult to detect any tumor-enhancing effect of reserpine. However, the incidences of multiple mammary gland tumors were significantly increased in dosed females from both lines. The incidence of mammary gland adenocarcinomas was significantly increased in TG-SH females receiving 5 p.p.m. reserpine. Reserpine did not induce any carcinogenic effects in non-transgenic mice. These results indicate that the transcriptional regulation of these three transgenes is a major determinant in the response to p-cresidine and reserpine. The use of transgenic models for the general detection of carcinogens may require lines in which appropriate genes are targeted for expression in many tissues, or lines in which critical genes have been inactivated.