Cellular processes of v-Src transformation revealed by gene profiling of primary cells--implications for human cancer.
BACKGROUND
Cell transformation by the Src tyrosine kinase is characterized by extensive changes in gene expression. In this study, we took advantage of several strains of the Rous sarcoma virus (RSV) to characterize the patterns of v-Src-dependent gene expression in two different primary cell types, namely chicken embryo fibroblasts (CEF) and chicken neuroretinal (CNR) cells. We identified a common set of v-Src regulated genes and assessed if their expression is associated with disease-free survival using several independent human tumor data sets.


METHODS
CEF and CNR cells were infected with transforming, non-transforming, and temperature sensitive mutants of RSV to identify the patterns of gene expression in response to v-Src-transformation. Microarray analysis was used to measure changes in gene expression and to define a common set of v-Src regulated genes (CSR genes) in CEF and CNR cells. A clustering enrichment regime using the CSR genes and two independent breast tumor data-sets was used to identify a 42-gene aggressive tumor gene signature. The aggressive gene signature was tested for its prognostic value by conducting survival analyses on six additional tumor data sets.


RESULTS
The analysis of CEF and CNR cells revealed that cell transformation by v-Src alters the expression of 6% of the protein coding genes of the genome. A common set of 175 v-Src regulated genes (CSR genes) was regulated in both CEF and CNR cells. Within the CSR gene set, a group of 42 v-Src inducible genes was associated with reduced disease- and metastasis-free survival in several independent patient cohorts with breast or lung cancer. Gene classes represented within this group include DNA replication, cell cycle, the DNA damage and stress responses, and blood vessel morphogenesis.


CONCLUSIONS
By studying the v-Src-dependent changes in gene expression in two types of primary cells, we identified a set of 42 inducible genes associated with poor prognosis in breast and lung cancer. The identification of these genes provides a set of biomarkers of aggressive tumor behavior and a framework for the study of cancer cells characterized by elevated Src kinase activity.
Department of Biology, McMaster University, 1280 Main street West, Hamilton, ON, L8S 4K1, Canada.
Bart M
BM
Maślikowski
Benjamin D
BD
Néel
Ying
Y
Wu
Lizhen
L
Wang
Natalie A
NA
Rodrigues
Germain
G
Gillet
Pierre-André
PA
Bédard
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D002642:Chick Embryo; D016000:Cluster Analysis; D015331:Cohort Studies; D018572:Disease-Free Survival; D005347:Fibroblasts / Q000166:cytology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016391:Genes, src; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D015688:Oncogene Protein pp60(v-src) / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D012160:Retina / Q000166:cytology
D015688:Oncogene Protein pp60(v-src)