uPAR enhances malignant potential of triple-negative breast cancer by directly interacting with uPA and IGF1R

BMC Cancer

Research Article

Manfred Schmitt¹  Michaela C. Huber²  Sara Molatore²  Natalie Falkenberg²  Michaela Aubele²  Rebecca Mall²  Katrin Lindner²  Annette Feuchtinger³  Axel Walch³  Herbert Braselmann⁴  Eva Gross⁵ 

[1] Clinical Research Unit, Department of Obstetrics and Gynecology, Technische Universität München, Ismaninger Strasse 22, 81675, München, Germany;Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany;Research Unit of Analytical Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany;Research Unit of Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany;Tumor Genetics Unit, Department of Obstetrics and Gynecology, Technische Universität München, Ismaninger Strasse 22, 81675, München, Germany;

关键词: IGF-1R;    TNBC;    Prognostic impact;    uPAR interactome;    uPAS;    uPA system;   

DOI  :  10.1186/s12885-016-2663-9

 received in 2016-01-20, accepted in 2016-08-03,  发布年份 2016

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s). 2016