Abstract
Triple-negative breast cancer (TNBC) cannot be treated with current hormonal therapies and has a higher risk of relapse than other breast cancers. To identify potential therapeutic targets for TNBC, we conducted microRNA sequencing (RNA-Seq) in human TNBC specimens and tumor-matched controls. We found that growth differentiation factor-10 (GDF10), a member of the TGF-β superfamily, was downregulated in tumor samples. Further analysis of GDF10 expression in a larger set of clinical TNBC samples using qPCR confirmed its downregulation and association with parameters of disease severity. Using human-derived TNBC cell lines, we carried out GDF10 under- and overexpression experiments, which showed that GDF10 loss promoted cell proliferation and invasion. By contrast, overexpression of GDF10 inhibited proliferation, invasion, and epithelial mesenchymal transition (EMT) via upregulation of Smad7 and E-Cadherin, downregulation of p-Smad2 and N-Cadherin, and reduction of nuclear Smad4 expression. In addition, overexpression of GDF10 reduced tumor burden and induced apoptosis in a TNBC xenograft mouse model. These findings indicate that GDF10 acts as a tumor suppressor in mammary epithelial cells that limits proliferation and suppresses EMT. Efforts aimed at restoring GDF10 expression may thus bring a long-sought therapeutic alternative in the treatment of patients with TNBC.
Highlights
Breast cancer is a heterogeneous disease, and a leading cause of death among women worldwide [1, 2]
56 downregulated mRNAs were detected in Triple-negative breast cancer (TNBC) samples relative to controls. These differentially expressed genes (DEGs) were visualized in MA and Volcano plots with the criteria set as false discovery rate (FDR) < 0.01 or log2 fold-change (FC) ≥ 2 (Figure 1B)
Among the DEGs detected by RNAseq in clinical TNBC specimens we focused on growth differentiation factor-10 (GDF10), a secreted transforming growth factor-β (TGF-β) receptor ligand with growth factor activity whose downregulation was shown to contribute to oral carcinogenesis [12]
Summary
Breast cancer is a heterogeneous disease, and a leading cause of death among women worldwide [1, 2]. Based on molecular marker variants, breast cancers are classified into various subtypes [1]. Triple‐negative breast cancer (TNBC) characterized by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression deficiency is the most aggressive form [1, 3, 4]. Patients with TNBC generally have poorer prognosis due to increased risks of local recurrence and distant metastasis [5, 6]. The challenge of treating TNBC resides in its heterogeneity, the lack of specific molecular targets, and development of resistance to systemic chemotherapy [7]. Novel effective therapies for TNBC are imminently needed
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