Genetic Diversity of Spontaneously Developed Primary and Metastatic Mammary Tumor Cells in Mice

Abstract

Metastatic cells are often considered to be clonal derivatives of one of the primary tumor cell subpopulations. To determine if the cells of spontaneously developed lung nodules in a mammary tumor-bearing mouse represent the major or minor population of the cells in the primary tumor, comparisons were made of the pattern of their mouse mammary tumor virus (MMTV) proviral integrations, and their insertional mutations of the mouse mammary tumor proto-oncogenes, int-1 and int-2. Of the 78 tumor-bearing C3H/He mice sacrificed, seven mice showed metastatic lung nodules, but only four mice had nodule tissues adequate for the present analysis. Examination of the primary tumors and the corresponding lung nodules of these four mice revealed that the number of newly integrated MMTV proviruses and their sites of integration in the genomic DNAs of primary tumors and tumor nodules were variable, and that the int-1 gene was disrupted in three of the primary tumors but not in any of the metastasized tumor tissue. These results support the notion that, at least in some mice, the majority of cells constituting the primary mammary tumors and the corresponding metastases are of different genotypes and raise the possibility that the activation of different int-proto-oncogenes may be involved in the genesis of different cell subpopulations including metastatic cells in the same mouse.