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.