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 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.
Asamoto
Makoto
M
Experimental Pathology and Chemotherapy Division, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan. htsuda@gan2.ncc.go.jp
Ota
Tomonori
T
Toriyama-Baba
Hiroyasu
H
Hokaiwado
Naomi
N
Naito
Akihiro
A
Tsuda
Hiroyuki
H
D000230:Adenocarcinoma / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D030801:Animals, Genetically Modified; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D002273:Carcinogens / Q000633:toxicity; D053138:Cyclohexenes; D004967:Estrogens / Q000502:physiology; D005260:Female; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D000077222:Limonene; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008770:Methylnitrosourea / Q000633:toxicity; D009376:Neoplasms, Hormone-Dependent / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D010052:Ovariectomy; D017368:Protein Prenylation / Q000187:drug effects; D000090063:Proto-Oncogene Mas; D051381:Rats; D017207:Rats, Sprague-Dawley; D013729:Terpenes / Q000627:therapeutic use*
D000972:Antineoplastic Agents, Phytogenic; D002273:Carcinogens; D053138:Cyclohexenes; D004967:Estrogens; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D013729:Terpenes; D008770:Methylnitrosourea; D000077222:Limonene