Item

Abstract

Deletions at the C-terminus of the proto-oncogene protein c-Src kinase are characteristic of the viral oncogene protein v-Src and are present in some advanced human colon cancers. They are associated with increased kinase activity and elevated cellular invasiveness. Here, we analyzed the mRNA expression signature of a constitutively active C-terminal mutant of c-Src, c-Src(mt), in comparison to its wildtype protein, c-Src(wt), expressed in the human non-transformed breast epithelial cell line MCF-10A. We demonstrated previously that the mutant changed migratory and metastatic properties. Genome-wide transcriptome analysis revealed that c-Src(mt) deregulated the expression levels of about 430 mRNAs whose gene products are mainly involved in the cellular processes of migration and adhesion, apoptosis and protein synthesis. More than 80% of these genes have previously been linked to cellular migration, while the others play roles, for instance, in RNA transport and splicing processes. Consistent with the transcriptome data, c-Src(mt)-, but not c-Src(wt)-expressing cells showed the capacity to metastasize into mouse lung tissue in vivo. The mRNA expression profile of c- Src(mt)-expressing cells shows significant overlap with that of various primary human tumor samples, perhaps reflecting elevated Src activity in some cancerous cells. Expression of c- Src(mt) lead to elevated migratory potential. We used this model system to analyze the transcriptional changes associated with an invasive cellular phenotype. We identified genes and pathways deregulated by c-Src(mt) as biomarkers with potential interest for diagnostics or therapy of metastatic cells.