Abstract
IntroductionMetastases remain the primary cause of cancer-related death. The acquisition of invasive tumour cell behaviour is thought to be a cornerstone of the metastatic cascade. Therefore, gene signatures related to invasiveness could aid in stratifying patients according to their prognostic profile. In the present study we aimed at identifying an invasiveness gene signature and investigated its biological relevance in breast cancer.Methods & ResultsWe collected a set of published gene signatures related to cell motility and invasion. Using this collection, we identified 16 genes that were represented at a higher frequency than observed by coincidence, hereafter named the core invasiveness gene signature. Principal component analysis showed that these overrepresented genes were able to segregate invasive and non-invasive breast cancer cell lines, outperforming sets of 16 randomly selected genes (all P<0.001). When applied onto additional data sets, the expression of the core invasiveness gene signature was significantly elevated in cell lines forced to undergo epithelial-mesenchymal transition. The link between core invasiveness gene expression and epithelial-mesenchymal transition was also confirmed in a dataset consisting of 2420 human breast cancer samples. Univariate and multivariate Cox regression analysis demonstrated that CIG expression is not associated with a shorter distant metastasis free survival interval (HR = 0.956, 95%C.I. = 0.896–1.019, P = 0.186).DiscussionThese data demonstrate that we have identified a set of core invasiveness genes, the expression of which is associated with epithelial-mesenchymal transition in breast cancer cell lines and in human tissue samples. Despite the connection between epithelial-mesenchymal transition and invasive tumour cell behaviour, we were unable to demonstrate a link between the core invasiveness gene signature and enhanced metastatic potential.
Highlights
Metastases remain the primary cause of cancer-related death
We identified 16 genes that were represented at a higher frequency than observed by coincidence, hereafter named the core invasiveness gene signature
When applied onto additional data sets, the expression of the core invasiveness gene signature was significantly elevated in cell lines forced to undergo epithelial-mesenchymal transition
Summary
Metastases remain the primary cause of cancer-related death. The acquisition of invasive tumour cell behaviour is thought to be a cornerstone of the metastatic cascade. In the present study we aimed at identifying an invasiveness gene signature and investigated its biological relevance in breast cancer. It is not the primary tumour that is lethal but the development of distant metastases. Tumour cells need to break away from the primary site to bridge the gap with the surrounding lymph or blood vessels. Numerous biological processes including cell motility, the acquisition of an invasive phenotype by cancer cells, angiogenesis and anti-apoptosis orchestrate the metastatic process [2][3]. One of the first steps of the metastatic cascade is the acquisition of a motile and invasive phenotype by cancer cells. It has been recognized that cancer cell invasion is a heterogeneous process covering at least five distinct patterns including rounded/ amoeboid migration, Epithelial-Mesenchymal Transition (EMT)
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