Carcinogenesis, Vol. 21, No. 2, 243-249,
February 2000
© 2000 Oxford University Press
Carcinogenesis |
Transgenic rats carrying human c-Ha-ras proto-oncogenes are highly susceptible to N-methyl-N-nitrosourea mammary carcinogenesis
Experimental Pathology and Chemotherapy Division,
1 Genetics Division and
2 Oncogene Division, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
A rat line carrying three copies of the human c-Ha-ras proto-oncogene, including its own promoter region, was established and designated Hras128. Expression of the transgene was detected in all organs examined from Hras128 rats by northern blot analysis. To examine its influence on susceptibility to N-methyl-N-nitrosourea (MNU)-induced mammary carcinogenesis, female rats were treated with 50 mg/kg MNU i.v. at 50 days of age. All 22 Hras128 transgenic rats rapidly developed multiple and large mammary carcinomas within as little as 8 weeks after MNU treatment (14.1 tumors/rat, average diameter 16.4 mm). In contrast, 24 non-transgenic littermates developed no or only small tumors (0.46 tumors/rat, average diameter 7.4 mm) within this period. PCR–restriction fragment length polymorphism (RFLP) analysis and direct sequencing for the transduced human c-Ha-ras proto-oncogene indicated that 38 out of 44 tumors (86.4%) contained cells with mutations at codon 12 in exon 1. However, the signal densities of the mutated bands observed in the RFLP analyses revealed the presence of mixed populations of mutated and non-mutated cells in the tumors, the latter being in the majority. PCR–single strand conformation polymorphism analysis detected no mutations in codons 12 or 61 of the endogenous rat c-Ha-ras gene of Hras128 rat tumors. The results thus indicate that rats carrying the transduced human c-Ha-ras proto-oncogene are highly susceptible to MNU-induced mammary carcinogenesis and that this is not primarily due to mutations of the transgene or endogenous c-Ha-ras gene.
Abbreviations: DMBA, 7,12-dimethylbenz[a]anthracene; GST, glutathione S-transferase; MNU, N-methyl-N-nitrosourea; RFLP, restriction fragment length polymorphism; SSCP, single strand conformation polymorphism.
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