Disrupting VEGF-A paracrine and autocrine loops by targeting SHP-1 suppresses triple negative breast cancer metastasis
Journal
Scientific Reports
Journal Volume
6
Date Issued
2016
Author(s)
Su J.-C.
Mar A.-C.
Wu S.-H.
Tai W.-T.
Chu P.-Y.
Wu C.-Y.
Tseng L.-M.
Lee T.-C.
Chen K.-F.
Liu C.-Y.
Shiau C.-W.
Abstract
Patients with triple-negative breast cancer (TNBC) had an increased likelihood of distant recurrence and death, as compared with those with non-TNBC subtype. Regorafenib is a multi-receptor tyrosine kinase (RTK) inhibitor targeting oncogenesis and has been approved for metastatic colorectal cancer and advanced gastrointestinal stromal tumor. Recent studies suggest regorafenib acts as a SHP-1 phosphatase agonist. Here, we investigated the potential of regorafenib to suppress metastasis of TNBC cells through targeting SHP-1/p-STAT3/VEGF-A axis. We found a significant correlation between cancer cell migration and SHP-1/p-STAT3/VEGF-A expression in human TNBC cells. Clinically, high VEGF-A expression is associated with worse disease-free and distant metastasis-free survival. Regorafenib induced significant anti-migratory effects, in association with downregulation of p-STAT3 and VEGF-A. To exclude the role of RTK inhibition in regorafenib-induced anti-metastasis, we synthesized a regorafenib derivative, SC-78, that had minimal effect on VEGFR2 and PDGFR kinase inhibition, while having more potent effects on SHP-1 activation. SC-78 demonstrated superior in vitro and in vivo anti-migration to regorafenib. Furthermore, VEGF-A dependent autocrine/paracrine loops were disrupted by regorafenib and SC-78. This study implies that SHP-1/p-STAT3/VEGF-A axis is a potential therapeutic target for metastatic TNBC, and the more potent SC-78 may be a promising lead for suppressing metastasis of TNBC.
SDGs
Other Subjects
carbanilamide derivative; protein tyrosine phosphatase SHP 1; PTPN6 protein, human; pyridine derivative; regorafenib; STAT3 protein; vasculotropin A; animal; autocrine effect; cell motion; drug effect; drug screening; female; genetics; human; Kaplan Meier method; metabolism; metastasis; nude mouse; paracrine signaling; triple negative breast cancer; tumor cell line; Animals; Autocrine Communication; Cell Line, Tumor; Cell Movement; Female; Humans; Kaplan-Meier Estimate; Mice, Nude; Neoplasm Metastasis; Paracrine Communication; Phenylurea Compounds; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Pyridines; STAT3 Transcription Factor; Triple Negative Breast Neoplasms; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays
Type
journal article