Genetic Instability and the Acquisition of Metastatic Ability by Rat Mammary Cancer Cells following v-H-ras Oncogene Transfection1

When nonmetastatic dimethylbenzanthracene-induced rat mammary cancer cells (KM( I ) were transfected with a control plasmili containing the neomycin resistance gene (i.e.. Neo/Only), none of the five clonal Neo/Only transfectants isolated and characterized was metastatic, only one of five had a single structural chromosomal abnormality, and only one of five had a single numerical chromosomal change not present in the untransfected parental RMC1 cells. In contrast, when RMC1 cells were transfected with a plasmili containing both the neo resistance and mutated \-l l-ra.v oncogene (i.e.. Neo/Ras), four of nine clonal Neo/Ras transfectants isolated and characterized were highly metastatic, and all nine had multiple structural and/or additional numerical chromosomal abnormalities. The frequency of transfectants which had structural and/ or additional numerical chromosomal changes in Neo/Ras transfectants was significantly higher than that in Neo/Only transfectants (/' < 0.05). In addition, seven of nine Neo/Ras transfectants had structural abnor malities in chromosome 1, whereas none of five Neo/Only transfectants had such abnormalities (/' < 0.05). All four Neo/Ras transfectants that were highly metastatic had structural aberrations involving a gain in chromsome 4. In contrast, none of the three Neo/Ras transfectants which were of low metastatic ability had a similar aberration involving chro mosome 4. Correlation between a gain in chromosome 4 and a gain of high metastatic ability was significant (/* < 0.05). These results demon strate that, when RMC1 cells are transfected with v-H-ras, transfectants expressing the mutated v-H-ras p21 become genetically unstable and undergo chromosomal changes. These studies suggest that, if the appro priate chromosomal changes occur, these i-lI-ra.v transfectants acquire high metastatic ability.