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.
Highlights
triple-negative breast cancer (TNBC) occurs in approximately 15% to 20% of breast cancers worldwide, mostly in young women and is clinically defined by the lack of expression of the receptors for estrogen and progesterone (ER/progesterone receptor (PR)) and the absent overexpression of the human epidermal growth factor receptor 2 (HER2) [1]
Since there is still a lack of targeted therapies in TNBC, the uPA system as well as novel interacting partners of uPAR or associated proteins are of great interest as candidates for therapeutic biomarkers in this aggressive tumor entity
To explore the uPA system as a potential therapeutic target system and associated proteins, here, cysteine-rich angiogenic inducer 61 (Cyr61) and Y-box-binding protein 1 (YB-1) were identified as novel interaction partners based on analyzing an uPAR-co-IP-precipitate using mass spectrometry
Summary
TNBC occurs in approximately 15% to 20% of breast cancers worldwide, mostly in young women and is clinically defined by the lack of expression of the receptors for estrogen and progesterone (ER/PR) and the absent overexpression of the human epidermal growth factor receptor 2 (HER2) [1]. The uPAS plays an important role in cell movement during natural processes including wound healing, clot lysis and tissue remodeling leading to activation of further components and degradation of the extracellular matrix. In cancer, it is associated with enhanced migration and invasion of tumor cells and with a bad prognosis for the patients [7]. The uPAS components with interacting proteins and co-factors are interesting candidates as novel molecular targets or prognostic/predictive biomarkers for a tailored and improved therapy of TNBC. The scope of the present study was to identify novel interacting partners of uPAR that may be potential therapeutic targets or of clinical relevance. Based on immunohistochemical and clinical data of the patients, Cyr and YB-1 have been shown to be of clinical relevance in breast cancer including TNBC and may be promising therapeutic target
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