Mammary Carcinomas Induced in Human c‐Ha‐ras Proto‐oncogene Transgenic Rats Are Estrogen‐independent, but Responsive to d‐Limonene Treatment

We have previously shown that transgenic rats carrying three copies of the human c‐Ha‐ras proto‐ oncogene (Hras128) are highly susceptible to N‐methyl‐N‐nitrosourea (MNU) mammary carcino‐ genesis. All transgenic rats treated with 50 mg/kgMNU, i.v. at 50 days of age, were found to rapidly develop multiple, large mammary carcinomas within as short a period as 8 weeks. In the present study, the effects of ovariectomy and treatment with d‐limonene, known to inhibit mammary carcinogenesis in non‐transgenic female rats, were investigated in Hras128 animals treated withMNU to clarify the role of the human c‐Ha‐ras proto‐oncogene and to characterize the induced mammary carcinomas. Although ovariectomy completely inhibited development of mammary carcinomas in their wild‐type counterparts, it did not affect either the incidence or the multiplicity of the mammary carcinomas in the Hras128 rats. On the other hand, treatment with d‐limonene, an inhibitor of ras protein isoprenylation, inhibited the breast tumor development. These results indicate that aberrant c‐Ha‐ras gene expression is involved in ovarian hormone‐independent growth and c‐Ha‐ras protein isoprenylation plays an important role in mammary carcinogenesis