Cyr61 and YB-1 are novel interacting partners of uPAR and elevate the malignancy of triple-negative breast cancer

// Michaela C. Huber 1 , Natalie Falkenberg 1 , Stefanie M. Hauck 2 , Markus Priller 2 , Herbert Braselmann 3 , Annette Feuchtinger 1, 4 , Axel Walch 1, 4 , Manfred Schmitt 5 , Michaela Aubele 1 1 Institute of Pathology, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Neuherberg 85764, Germany 2 Research Unit of Protein Science, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Neuherberg 85764, Germany 3 Research Unit of Radiation Cytogenetics, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Neuherberg 85764, Germany 4 Research Unit of Analytical Pathology, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Neuherberg 85764, Germany 5 Clinical Research Unit, Department of Obstetrics and Gynecology, Technische Universitat Munchen, Munchen 81675, Germany Correspondence to: Natalie Falkenberg, email: natalie.falkenberg@helmholtz-muenchen.de Keywords: TNBC, YBX1, CCN1, proximity ligation assay, PLA Received: February 26, 2016      Accepted: May 16, 2016      Published: June 6, 2016 ABSTRACT The triple-negative breast cancer (TNBC) is a very aggressive tumor type often occurring in young women and is associated with a bad prognosis for the patients. TNBC lacks established targets for breast cancer therapy, such as the estrogen receptor (ER), progesterone receptor (PR) and the human epidermal growth factor receptor 2 (HER2). Therefore, novel therapeutic targets and strategies are needed for an improved treatment of this breast cancer subtype. TNBC and respective cell lines often overexpress proteins of the urokinase plasminogen activator system (uPAS) including uPA, its receptor uPAR and inhibitor PAI-1, which together with co-factors contribute to the malignancy of TNBC. Here, two novel interacting partners of uPAR, the cysteine-rich angiogenic inducer 61 (Cyr61) and the Y-box-binding protein 1 (YB-1) were identified and their differential expression demonstrated in TNBC cells as well as in tumors. In the TNBC cohort, both interactors significantly correlated with expression levels of cathepsin B, c-Met and the tumor grade. In addition, expression levels of Cyr61 significantly correlated with cathepsin D (p=0.03), insulin receptor (p≤0.001), insulin-like growth factor receptor 1 (IGF1R, p=0.015) and also with YB-1 (p=0.0004) levels. The interactions of uPAR with Cyr61 significantly correlated with expression levels of tumor-promoting biomarkers including plasminogen (p=0.0014), cathepsin B (p=0.032), c-Met (p=0.0192) as well as with the tumor grade (p=0.02). In multivariate survival analysis, YB-1 showed independent prognostic value (p=0.01). As the novel interacting partners, also together with uPAR, contribute to tumor progression and metastasis, both may be potential therapeutic targets in breast cancer.