title: uPAR enhances malignant potential of triple-negative breast cancer by directly interacting with uPA and IGF1R.
abstract: 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. 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.
  
  
  
  Direct 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).
  
  
  
  Direct 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.
  
  
  
  Our 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.
authors: Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany.
authors: Michaela C
authors: MC
authors: Huber
authors: Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany.
authors: Rebecca
authors: R
authors: Mall
authors: Research Unit of Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany.
authors: Herbert
authors: H
authors: Braselmann
authors: Research Unit of Analytical Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany.
authors: Annette
authors: A
authors: Feuchtinger
authors: Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany.
authors: Sara
authors: S
authors: Molatore
authors: Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany.
authors: Katrin
authors: K
authors: Lindner
authors: Research Unit of Analytical Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany.
authors: Axel
authors: A
authors: Walch
authors: Tumor Genetics Unit, Department of Obstetrics and Gynecology, Technische Universität München, Ismaninger Strasse 22, 81675, München, Germany.
authors: Eva
authors: E
authors: Gross
authors: Clinical Research Unit, Department of Obstetrics and Gynecology, Technische Universität München, Ismaninger Strasse 22, 81675, München, Germany.
authors: Manfred
authors: M
authors: Schmitt
authors: Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany.
authors: Natalie
authors: N
authors: Falkenberg
authors: Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany. aubele@helmholtz-muenchen.de.
authors: Michaela
authors: M
authors: Aubele
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D060787:Neoplasm Grading; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
chemical_list: C000597236:IGF1R protein, human; C524898:PLAUR protein, human; D017451:Receptors, Somatomedin; D055293:Receptors, Urokinase Plasminogen Activator; D017526:Receptor, IGF Type 1; D014568:Urokinase-Type Plasminogen Activator
keywords: IGF-1R; Prognostic impact; TNBC; uPA system; uPAR interactome; uPAS