Pvm. Shekhar et Fr. Miller, CORRELATION OF DIFFERENCES IN MODULATION OF RAS EXPRESSION WITH METASTATIC COMPETENCE OF MOUSE MAMMARY-TUMOR SUBPOPULATIONS, Invasion & metastasis, 14(1-6), 1994, pp. 27-37
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.