Journal
CANCER RESEARCH
Volume 75, Issue 7, Pages 1275-1286Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-14-2387
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Funding
- National Natural Science Foundation of China [81202102, 90919032, 31370749, 31125012]
- Project for Innovative Research Team of Ministry of Education [IRT13085]
- Project of Applicative Basic Research and Advanced Technology of Tianjin Municipal Science and Technology Commission [13JCQNJC12100, 13JCYBJC21400]
- Specialized Research Fund for the Doctoral Program of Higher Education [20121202120018]
- Tianjin Municipal High School Science & Technology Foundation [20110102]
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SND1 is an AEG-1/MTDH/LYRIC-binding protein that is upregulated in numerous human cancers, where it has been assigned multiple functional roles. In this study, we report its association with the TGF beta 1 signaling pathway, which promotes epithelial-mesenchymal transition (EMT) in breast cancer. SND1 was upregulated in breast cancer tissues, in particular in primary invasive ductal carcinomas. Transcriptional activation of the SND1 gene was controlled by the TGF beta 1/Smad pathway, specifically by activation of the Smad2/Smad3 complex. The SND1 promoter region contained several Smad-specific recognition domains (RD motifs), which were recognized and bound by the Smad complex that enhanced the transcriptional activation of SND1. We found that SND1 promoted expression of the E3 ubiquitin ligase Smurf1, leading to RhoA ubiquitination and degradation. RhoA degradation in breast cancer cells disrupted F-actin cytoskeletal organization, reduced cell adhesion, increased cell migration and invasion, and promoted metastasis. Overall, our results define a novel role for SND1 in regulating breast tumorigenesis and metastasis. (C)2015 AACR.
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