Abstract
Tumour cell-extracellular matrix (ECM) interactions are fundamental for discrete steps in breast cancer progression. In particular, cancer cell adhesion to ECM proteins present in the microenvironment is critical for accelerating tumour growth and facilitating metastatic spread. To assess the utility of tumour cell-ECM adhesion as a means for discovering prognostic factors in breast cancer survival, here we perform a systematic phenotypic screen and characterise the adhesion properties of a panel of human HER2 amplified breast cancer cell lines across six ECM proteins commonly deregulated in breast cancer. We determine a gene expression signature that defines a subset of cell lines displaying impaired adhesion to laminin. Cells with impaired laminin adhesion showed an enrichment in genes associated with cell motility and molecular pathways linked to cytokine signalling and inflammation. Evaluation of this gene set in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort of 1,964 patients identifies the F12 and STC2 genes as independent prognostic factors for overall survival in breast cancer. Our study demonstrates the potential of in vitro cell adhesion screens as a novel approach for identifying prognostic factors for disease outcome.
Highlights
The extracellular matrix (ECM) in the mammary gland microenvironment undergoes dynamic remodelling and is deregulated during breast cancer progression [1, 2]
We employed automated image-based phenotypic screens to evaluate the manner in which HER2+ cells adhere to ECM molecules. 96-well www.impactjournals.com/oncotarget plates were pre-coated with six ECM components that are commonly deregulated in breast cancer with uncoated plastic as a negative control [25]
We show that the F12 and STC2 genes derived from a gene expression signature of impaired laminin adhesion are independent prognostic factors for overall survival in breast cancer
Summary
The extracellular matrix (ECM) in the mammary gland microenvironment undergoes dynamic remodelling and is deregulated during breast cancer progression [1, 2]. To address some of these challenges, large-scale ECM arrays have been developed to examine tumour cell-ECM interactions in a systematic and combinatorial manner [20]. This has led to the characterisation of key adhesive changes associated with metastatic progression in a mouse model of lung adenocarcinoma and provided the first demonstration that in vitro cell adhesion screens can be employed as a means to identify clinically meaningful biomarkers such as galectin-3 for tumour, node and metastasis (TMN) staging [20]
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