Mammary carcinomas induced in human c-Ha-ras proto-oncogene transgenic rats are estrogen-independent, but responsive to d-limonene treatment

Jpn J Cancer Res. 2002 Jan;93(1):32-5. doi: 10.1111/j.1349-7006.2002.tb01197.x.


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 carcinogenesis. All transgenic rats treated with 50 mg / kg MNU, 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 with MNU 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / chemically induced
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / prevention & control*
  • Animals
  • Animals, Genetically Modified
  • Antineoplastic Agents, Phytogenic / therapeutic use*
  • Carcinogens / toxicity
  • Cyclohexenes
  • Estrogens / physiology
  • Female
  • Genes, ras / physiology*
  • Humans
  • Limonene
  • Male
  • Mammary Neoplasms, Experimental / chemically induced
  • Mammary Neoplasms, Experimental / pathology
  • Mammary Neoplasms, Experimental / prevention & control*
  • Methylnitrosourea / toxicity
  • Neoplasms, Hormone-Dependent / chemically induced
  • Neoplasms, Hormone-Dependent / pathology
  • Neoplasms, Hormone-Dependent / prevention & control*
  • Ovariectomy*
  • Protein Prenylation / drug effects
  • Proto-Oncogene Mas
  • Rats
  • Rats, Sprague-Dawley
  • Terpenes / therapeutic use*


  • Antineoplastic Agents, Phytogenic
  • Carcinogens
  • Cyclohexenes
  • Estrogens
  • MAS1 protein, human
  • Proto-Oncogene Mas
  • Terpenes
  • Methylnitrosourea
  • Limonene