title: High susceptibility of human c-Ha-ras proto-oncogene transgenic rats to carcinogenesis: a cancer-prone animal model.
abstract: Transgenic animals carrying human c-Ha-ras proto-oncogene, v-Ha-ras transgenic mice, pim-1 transgenic mice and several knockout mice deficient of tumor suppressor genes, such as p53, have been shown to exhibit increased carcinogen susceptibility. As a result, studies into practical application and medium-term screening of environmental carcinogens are under way. Given the advantages of rat models characterized by larger organ size, abundant information regarding preneoplasias and virus-free constitution, we have concentrated on the generation of transgenic rats bearing copies of the human c-Ha-ras proto-oncogene and shown the Hras128 strain to be extremely sensitive to the induction of mammary carcinomas, and to a lesser extent, lesions in the urinary bladder, esophagus and skin. In most, if not all, the mammary cancers mutations of the transgene but not the endogenous H-ras gene are present, appearing to occur early in the process of tumorigenesis, which involves proliferation of cells in TEB and intraductal hyperplasia before carcinomas arise. Preliminary findings suggest that this is independent of endogenous ovarian hormones, although inhibited by soy isoflavones and promoted by atrazine and nonylphenols. Although further studies of the mechanisms are clearly necessary, the model appears to have great potential for screening purposes, not only for modifiers active in the breast, but also other organs where tumors characterized by ras gene mutations develop.
authors.affiliation: Department of Molecular Toxicology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-ku, Nagoya 467-8601, Japan. htsuda@med.nagoya-cu.ac.jp
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsuda
authors.forename: Katsumi
authors.initials: K
authors.lastname: Fukamachi
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Ohshima
authors.forename: Shinobu
authors.initials: S
authors.lastname: Ueda
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Matsuoka
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hamaguchi
authors.forename: Takamasa
authors.initials: T
authors.lastname: Ohnishi
authors.forename: Nobuo
authors.initials: N
authors.lastname: Takasuka
authors.forename: Akihiro
authors.initials: A
authors.lastname: Naito
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002273:Carcinogens / Q000494:pharmacology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004195:Disease Models, Animal; D004938:Esophageal Neoplasms / Q000209:etiology / Q000235:genetics; D005260:Female; D011905:Genes, ras / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000209:etiology / Q000235:genetics; D000090063:Proto-Oncogene Mas; D051381:Rats; D017207:Rats, Sprague-Dawley; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000209:etiology / Q000235:genetics
chemical_list: D002273:Carcinogens; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas