Abstract
150 Background: Triple-negative breast cancers (TNBC), which lack expression of estrogen (ER), progesterone (PR), and HER2 receptors are characterized by tumor tissue expression of the urokinase-type plasminogen activator receptor (uPAR) system. Methods: We evaluated uPAR and its interaction partners (uPAR-interactome) by immunohistochemistry (IHC) in tissue microarrays (TMA) prepared from ~300 TNBC tumor tissue specimens and in the TNBC model cell lines BT549 and MDA-MB231. Protein expression of 25 different factors constituting the uPAR-interactome was evaluated by IHC; several of the uPAR-protein complexes were identified employing the proximity ligation assay (PLA). Results were correlated with histomorphological parameters and survival of the patients. RNA interference was employed in the TNBC cell lines for several of the parameters assessed. To analyze effects of uPAR and/or uPA depletion on malignant cell behavior, proliferation, migration, and invasion assays as well as Western blot, PLA, immunoprecipitation, mass spectrometry, and immunohistochemistry were conducted. Results: After downregulation of uPAR and uPA in TNBC cell lines, significantly reduced cell proliferation, invasion, and migration were observed. Furthermore, interaction between uPAR and IGF1R (insulin-like growth factor1 receptor) was shown, and several novel interaction proteins of uPAR could be identified, such as Cyr61 (cysteine-rich angiogenic inducer61). In TNBC tumor specimens, association between uPAR expression and histological grade plus expression of cathepsin B, IGF1R, IR (insulin receptor), and plasminogen was shown. Expression of KLK4 (stromal) and Ki67 was correlated with disease-free survival of the patients. Presence of uPAR/IGF1R protein complexes was associated with histological grade, with the expression of PAI-1, Ki-67, p27, and cathepsin B. Conclusions: Our findings demonstrate that uPAR and its interacting partners, expressed in TNBC tumor tissues, may be considered as potential novel therapeutic targets for this fatal disease.
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