ラットおよびヒト乳腺発がんにおける一塩基不安定性(第13回公開シンポジウム「環境変異原と遺伝子不安定性」)

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Genomic instability plays important roles in carcinogenesis. To analyze point mutation rates (MRs) in rat mammary carcinomas, we established two cell lines from those induced in lacI-transgenic rats by 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine. The two cell lines showed 6-8 fold increases in the spontaneous point MRs of the endogenous hprt gene and 12-15 fold increases in the lacI transgene. Since the cell lines lacked microsatellite instability (MSI) and were capable of G/T mismatch-binding, the increase of spontaneous point MRs was considered to be due to a mechanism (s) different from mismatch repair insufficiency, and this type of genetic instability was termed as single nucleotide instability (SNI). SNI in the rat mammary carcinoma cell lines was characterized by an elevation of A : T to C : G transversions, which were rarely observed in normal mammary epithelial cells. The elevation of the A : T to C : G transversions was also present in the lacI gene of the primary carcinomas of the two cell lines, which suggested that the molecular abnormality present in the cell lines was already present in their primary carcinomas. Spontaneous point MRs of the hprt gene were measured in six human breast cancer cell lines, and an increase was found in five of them. These human breast cancer cell lines were reported to lack MSI, and were proficient in C/T mismatch binding. Therefore, it was shown that SNI existed also in five of the six human breast cancer cell lines. Inactivation of Mth1, the mammalian homologue of E. coli the MutT gene, and overexpression of the DNA polymerase κ, both of which were known to cause increases of A : T to C : G transversions, were analyzed in the rat mammary carcinoma cell lines and their primary carcinomas. However, neither of them was present. Considering that MSI is infrequent in human and rat mammary carcinomas, a wide role of SNI in the development of such tumors was suggested.
日本環境変異原学会の論文
2002-11-13

ラットおよびヒト乳腺発がんにおける一塩基不安定性(第13回公開シンポジウム「環境変異原と遺伝子不安定性」)

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