Correlation of differences in modulation of ras expression with metastatic competence of mouse mammary tumor...

The ras family of cellular oncogenes is one of the most frequently detected families of transformation-inducing genes in human solid tumors. The capacity of breast cancers to grow and metastasize have been related to enhanced expression of normal p21ras rather than the mutant form. Transformation in tumours that lack the mutant p21ras has been suggested to result from transcriptional deregulation of ras. cis-Acting sequence elements that participate in the regulation of gene expression in normal tissues and that could serve as potential targets for the deregulation of expression in tumors have been localized in several genes including c-myc and N-ras. Using a mouse mammary metastasis model system of closely related tumor subpopulations that vary in metastatic potential and with defined deficiencies, we show that c-Ha-ras plays 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 strong transcription enhancer activity that is differentially modulated by steroid hormones in metastatic and nonmetastatic subpopulations. Our results indicate that perturbations in the regulatory activities of cis-acting sequences such as the one we have identified may play an important role in governing oncogenic potency of Ha-ras through transcriptional control mechanisms.