Oncogenic potential of BRAF versus RAS

Mutations in the ERK pathway occur in approximately one-third of all human cancers and most often involve production of mutant RAS or BRAF. Several studies, including our own, have shown that mutations in the BRAF and RAS genes are generally mutually exclusive. This study was performed to determine the relative oncogenic potential of the BRAF and RAS oncogenes. BRAFV600E-, H-RASG12V-, and N-RASQ61R-transfected mouse embryonic fibroblasts (MEFs) that lack p53 (p53−/−) or contain mutations at codon 172 (p53R172H and p53R172P) were able to induce morphologically transformed foci in p53−/− and p53R172H MEFs but not in p53R172P MEFs. Interestingly, BRAFV600E was less potent than mutant H-RASG12V or N-RASQ61R was in cooperating with mutant p53 as the numbers and sizes of foci induced by BRAFV600E were significantly lower and smaller. In vitro growth characteristics and anchorage-independent growth of transfected MEFs corroborated the transformed phenotype, and in vivo tumorigenesis confirmed the results. These results indicate that mutant BRAFV600E is weakly oncogenic compared with mutant RAS and that they both cooperate with p53−/− and p53R172H but not with p53R172P in oncogenic transformation.