Research Paper Volume 11, Issue 10 pp 3298—3314
GDF10 inhibits proliferation and epithelial-mesenchymal transition in triple‐negative breast cancer via upregulation of Smad7
- 1 Department of Breast Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, China
- 2 Prenatal Diagnosis Center, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, China
- 3 Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, China
- 4 Equal Contribution
Received: November 13, 2018 Accepted: May 31, 2019 Published: May 31, 2019
https://doi.org/10.18632/aging.101983How to Cite
Copyright: Zhou et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.