Transcriptional signature induced by a metastasis‐promoting c‐Src mutant in a human breast cell line

Abstract

Deletions at the C-terminus of the proto-oncogene protein c-Src kinase are found in the viral oncogene protein v-Src as well as in some advanced human colon cancers. They are associated with increased kinase activity and cellular invasiveness. Here, we analyzed the mRNA expression signature of a constitutively active C-terminal mutant of c-Src, c-Src(mt), in comparison with its wild-type protein, c-Src(wt), in the human non-transformed breast epithelial cell line MCF-10A. We demonstrated previously that the mutant altered migratory and metastatic properties. Genome-wide transcriptome analysis revealed that c-Src(mt) de-regulated the expression levels of approximately 430 mRNAs whose gene products are mainly involved in the cellular processes of migration and adhesion, apoptosis and protein synthesis. 82.9% of these genes have previously been linked to cellular migration, while the others play roles in RNA transport and splicing processes, for instance. Consistent with the transcriptome data, cells expressing c-Src(mt), but not those expressing c-Src(wt), showed the capacity to metastasize into the lungs of mice in vivo. The mRNA expression profile of c-Src(mt)-expressing cells shows significant overlap with that of various primary human tumor samples, possibly reflecting elevated Src activity in some cancerous cells. Expression of c-Src(mt) led to elevated migratory potential. We used this model system to analyze the transcriptional changes associated with an invasive cellular phenotype. These genes and pathways de-regulated by c-Src(mt) may provide suitable biomarkers or targets of therapeutic approaches for metastatic cells. DATABASE: This project was submitted to the National Center for Biotechnology Information BioProject under ID PRJNA288540. The Illumina RNA-Seq reads are available in the National Center for Biotechnology Information Sequence Read Archive under study ID SRP060008 with accession numbers SRS977414 for MCF-10A cells, SRS977717 for mock cells, SRS978053 for c-Src(wt) cells and SRS978046 for c-Src(mt) cells

YAP/TAZ Activation as a Target for Treating Metastatic Cancer

“…Src was the first proto-oncogene discovered and its role in cancer progression and metastasis is well established. Activation of Src can promote transformation, invasion, tumor growth, and metastasis [ 227 , 228 , 229 , 230 , 231 , 232 , 233 , 234 , 235 , 236 , 237 , 238 , 239 , 240 ], and several studies have found that Src inhibition can reduce metastasis formation in vivo [ 228 , 232 , 234 , 235 , 236 , 238 ]. Src levels or activity are increased in many human cancers [ 219 , 230 , 237 , 241 , 242 , 243 ], and Src is essential for outgrowth of disseminated tumor cells in the bone marrow [ 240 ].…”

Src promotes castration-recurrent prostate cancer through androgen receptor-dependent canonical and non-canonical transcriptional signatures

“…Of the gene products that are downregulated in this list, OPRK1 likely controls neuroendocrine differentiation [74], NOV suppresses androgen-independent PC growth [71], CAMK2N1 suppresses growth factor-induced PI3K and MEK/ERK proliferative signaling in PC cell lines [64], STAC likely modulates proliferative signaling through its SH3 and cysteine-rich domains, butyrylcholinesterase (BCHE) likely suppresses cholinergic stimulation of PC proliferation [68], and loss-of-function mutations in sucrase-isomaltase (SI) have been associated with cancer-promoting metabolic reprogramming [103]. Importantly, in LNCaP cells, Src mainly affects gene expression specific to prostate epithelial cell pathways since there are few in common with those regulated by activated Src in MCF-10A breast epithelial cells [104]. …”

Inhibition of eEF2K synergizes with glutaminase inhibitors or 4EBP1 depletion to suppress growth of triple-negative breast cancer cells

“…6B). Collagen chain components including COL28A1 are up-regulated in a transcriptional signature induced by a metastasis-promoting c-Src mutant in human breast cells 30 . In addition, COL1A1 promotes cell migration in vitro and metastasis in colorectal cancer by regulating the WNT/PCP pathway 31 .…”