Abstract
Breast cancer is a heterogeneous disease characterized by multiple genetic alterations leading to the activation of growth factor signaling pathways that promote cell proliferation. Platelet-derived growth factor-C (PDGF-C) is overexpressed in various malignancies; however, the involvement of PDGF-C in breast cancers and the mechanisms underlying PDGF-C deregulation remain unclear. Here, we show that PDGF-C is overexpressed in clinical breast cancers and correlates with poor prognosis. PDGF-C up-regulation was mediated by the human embryonic lethal abnormal vision-like protein HuR, which stabilizes the PDGF-C transcript by binding to two predicted AU-rich elements (AREs) in the 3'-untranslated region (3'-UTR). HuR is up-regulated in hydrogen peroxide-treated or ultraviolet-irradiated breast cancer cells. Clinically, HuR levels are correlated with PDGF-C expression and histological grade or pathological tumor-node-metastasis (pTNM) stage. Our findings reveal a novel mechanism underlying HuR-mediated breast cancer progression, and suggest that HuR and PDGF-C are potential molecular candidates for targeted therapy of breast cancers.
Highlights
Growth factors and their downstream signaling pathways play important roles in the uncontrolled proliferation and apoptosis resistance characteristic of malignant cells [1,2,3]
Patients were grouped according to the level of Platelet-derived growth factor-C (PDGF-C) expression, as determined by immunohistochemical staining, which showed that PDGF-C-high breast carcinomas were associated with short disease-free survival compared with PDGF-C-low or -negative breast cancers (Figure 1B)
We showed that PDGF-C expression was positively correlated with late-stage clinical breast cancers
Summary
Growth factors and their downstream signaling pathways play important roles in the uncontrolled proliferation and apoptosis resistance characteristic of malignant cells [1,2,3]. Platelet-derived growth factor-C (PDGF-C) is a new member of the PDGF family that is expressed in epithelial cells, muscle, and neuronal progenitors [4]. Dimerizes and activates several canonical signaling pathways such as phosphoinositide-3-kinase Akt (PI3K/Akt), Ras mitogen-activated protein kinase (Ras/MAPK), and phospholipase C-γ/Ca2+ (PLC-γ/Ca2+), promoting cell survival, proliferation, and focal adhesion [4,5]. Aberrant expression of PDGF-C is implicated in various malignancies, in particular glioblastoma and Ewing family sarcoma [4,6,7]. The regulation of PDGF-C and the mechanisms underlying its up-regulation in carcinoma cells remain largely unknown
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