title: Disrupting VEGF-A paracrine and autocrine loops by targeting SHP-1 suppresses triple negative breast cancer metastasis.
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.
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.|Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan.
authors.forename: Jung-Chen
authors.initials: JC
authors.lastname: Su
authors.affiliation: Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Ai-Chung
authors.initials: AC
authors.lastname: Mar
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Szu-Hsien
authors.initials: SH
authors.lastname: Wu
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.|National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Wei-Tien
authors.initials: WT
authors.lastname: Tai
authors.affiliation: School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.|Department of Pathology, Show Chwan Memorial Hospital, Changhua City, Taiwan.
authors.forename: Pei-Yi
authors.initials: PY
authors.lastname: Chu
authors.affiliation: Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.|School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chia-Yun
authors.initials: CY
authors.lastname: Wu
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Ling-Ming
authors.initials: LM
authors.lastname: Tseng
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Te-Chang
authors.initials: TC
authors.lastname: Lee
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.|National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Kuen-Feng
authors.initials: KF
authors.lastname: Chen
authors.affiliation: Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.|School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Liu
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan.
authors.forename: Hao-Chieh
authors.initials: HC
authors.lastname: Chiu
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Shiau
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D019899:Paracrine Communication / Q000187:drug effects; D010671:Phenylurea Compounds / Q000494:pharmacology*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D010671:Phenylurea Compounds; D011725:Pyridines; D050796:STAT3 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; C559147:regorafenib; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6