Abstract
BackgroundDue to lack of a targeted therapy for the triple-negative breast cancer (TNBC) patients, it is important to explore this aggressive breast cancer type in more detail and to establish novel therapeutic approaches. TNBC is defined negative for the protein expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). One prominent feature of this cancer type is the frequent overexpression of major components of the urokinase-type plasminogen activator system (uPAS) including uPA, its receptor uPAR and the inhibitor PAI-1, which may be valuable as therapeutic targets.MethodsDirect interactions of uPAR with interactors were demonstrated by immunoprecipitations and proximity ligation assays. For stable knockdowns of target proteins, lentiviral vectors were used and the effects were analysed by immunoblottings and using in vitro cell viability, migration and invasion assays. Immunohistochemical and statistical analyses of biomarkers and clinical parameters were conducted in a TNBC cohort (n = 174).ResultsDirect tumour-promoting interactions of uPAR with uPA and the insulin-like growth factor receptor 1 (IGF1R) were shown in TNBC cells and these interactions were significantly reduced (p = 0.001) when uPAR was downregulated. The combined knockdown of uPAR and uPA or IGF1R additively and significantly reduced cell viability, migration and invasion of the model cell lines. In TNBC tissue, the complexes formed by uPAR with uPA or with IGF1R significantly correlated with the histological grade (p = 0.0019) as well as with cathepsin B and D (p ≤ 0.0001) that are implicated in cell invasion and metastasis.ConclusionsOur outcomes show that not only overexpressed biomarkers promote tumourigenesis, but rather their interactions further potentiate tumour progression. This study emphasises the potential of combined approaches targeting uPAR and its interactors with regard to an improved therapy of TNBC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2663-9) contains supplementary material, which is available to authorized users.
Highlights
Due to lack of a targeted therapy for the triple-negative breast cancer (TNBC) patients, it is important to explore this aggressive breast cancer type in more detail and to establish novel therapeutic approaches
Results urokinase-type plasminogen activator (uPAR), insulin-like growth factor receptor 1 (IGF1R) and hepatocyte growth factor receptor (c-Met) are significantly co-overexpressed in TNBC samples and breast cancer cell lines To select TNBC tumour samples for this study, the expression of markers of the urokinase-type plasminogen activator (uPA) system and related tumour-promoting proteins was determined by IHC analysis
Impeding the complexes of uPAR with uPA or IGF1R may strongly inhibit tumour progression in vivo by treating TNBC patients with inhibitors targeting these biomarkers in combination
Summary
Due to lack of a targeted therapy for the triple-negative breast cancer (TNBC) patients, it is important to explore this aggressive breast cancer type in more detail and to establish novel therapeutic approaches. It has been shown that strongly invasive TNBC cells and respective cell lines use this natural process and enhance their invasive capacity through overexpression of uPAR, uPA or MMPs [9, 15]. Depending on their cellular context and expression levels, IR, IGF1R, EGFR, c-Met and uPAR promote malignancy through cooperating with each other and may be promising candidates for an improved cancer therapy [13]. Since uPAR is solely associated to the plasma membrane by a glycosylphosphatidyl inositol (GPI) anchor, interactions with membrane-spanning receptors may enable uPAR-mediated intracellular signalling as well
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