Single nucleotide instability: a wide involvement in human and rat mammary carcinogenesis?

Abstract

Genetic instability plays important roles in carcinogenesis. In two cell lines which we established from mammary carcinomas induced in lacI-transgenic rats by 2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine (PhIP), spontaneous point mutation rates (MRs) of the endogenous hypoxanthine–guanine phosphoribosyltransferase ( hprt) gene and lacI transgene were found to be increased. The two rat mammary carcinoma cell lines lacked microsatellite instability (MSI), and nuclear extracts from them were proficient in 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 the elevation of A:T to C:G transversions of the hprt and lacI genes, which were rarely observed in normal mammary epithelial cells. The elevation of 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. Mth1 mutation, which is known to cause elevation of A:T to C:G transversions, was analyzed in the 2 cell lines and in 11 primary PhIP-induced mammary carcinomas, but no mutations were observed. Finally, spontaneous point MRs of the hprt gene were measured in six human breast cancer cell lines, and increase was found in five of them. These human breast cancer cell lines were proficient in G/T mismatch binding, and were reported to lack MSI. SNI was suggested to play a wide involvement in human and rat mammary carcinogenesis.