CORRELATION OF DIFFERENCES IN MODULATION OF RAS EXPRESSION WITH METASTATIC COMPETENCE OF MOUSE MAMMARY-TUMOR SUBPOPULATIONS

The ras family of cellular oncogenes is one of the most frequently det ected families of transformation-inducing genes in human solid tumors. The capacity of breast cancers to grow and metastasize have been rela ted to enhanced expression of normal p21(ras) rather than the mutant f orm. Transformation in tumors that lack the mutant p21(ras) has been s uggested to result from transcriptional deregulation of ras. cis-Actin g sequence elements that participate in the regulation of gene express ion in normal tissues and that could serve as potential targets for th e deregulation of expression in tumors have been localized in several genes including c-myc and N-ras. Using a mouse mammary metastasis mode l system of closely related tumor subpopulations that vary in metastat ic potential and with defined deficiencies, we show that c-Ha-ras play s a prominent role as a metastasis-modulating gene in this system. We have identified a highly conserved cis-acting sequence element in the first intron of the mouse and rat, and in the first exon of Ha- and Ki -ras genes of human, mouse and rat. This regulatory sequence confers s trong transcription enhancer activity that is differentially modulated by steroid hormones in metastatic and nonmetastatic subpopulations. O ur results indicate that perturbations in the regulatory activities of cis-acting sequences such as the one we have identified may play an i mportant role in governing oncogenic potency of Ha-ras through transcr iptional control mechanisms.