title: Sorafenib analogue SC-60 induces apoptosis through the SHP-1/STAT3 pathway and enhances docetaxel cytotoxicity in triple-negative breast cancer cells.
abstract: Recurrent triple-negative breast cancer (TNBC) needs new therapeutic targets. Src homology region 2 domain-containing phosphatase-1 (SHP-1) can act as a tumor suppressor by dephosphorylating oncogenic kinases. One major target of SHP-1 is STAT3, which is highly activated in TNBC. In this study, we tested a sorafenib analogue SC-60, which lacks angiokinase inhibition activity, but acts as a SHP-1 agonist, in TNBC cells. SC-60 inhibited proliferation and induced apoptosis by dephosphorylating STAT3 in both a dose- and time-dependent manner in TNBC cells (MDA-MB-231, MDA-MB-468, and HCC1937). By contrast, ectopic expression of STAT3 rescued the anticancer effect induced by SC-60. SC-60 also increased the SHP-1 activity, but this effect was inhibited when the N-SH2 domain (DN1) was deleted or with SHP-1 point mutation (D61A), implying that SHP-1 is the major target of SC-60 in TNBC. The use of SC-60 in combination with docetaxel synergized the anticancer effect induced by SC-60 through the SHP-1/STAT3 pathway in TNBC cells. Importantly, SC-60 also displayed a significant antitumor effect in an MDA-MB-468 xenograft model by modulating the SHP-1/STAT3 axis, indicating the anticancer potential of SC-60 in TNBC treatment. Targeting SHP-1/p-STAT3 and the potential combination of SHP-1 agonist with chemotherapeutic docetaxel is a feasible therapeutic strategy for TNBC.
authors.affiliation: Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taiwan.|Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taiwan.|School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Liu
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: Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taiwan.|Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taiwan.
authors.forename: Tzu-Ting
authors.initials: TT
authors.lastname: Huang
authors.affiliation: Department of Pathology, Show Chwan Memorial Hospital, Changhua, Taiwan.|School of Medicine, College of Medicine, Fu-Jen Catholic University, Xinzhuang, New Taipei City, Taiwan.
authors.forename: Pei-Yi
authors.initials: PY
authors.lastname: Chu
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Division of Hematology & Oncology, Department of Medicine, Yang-Ming Branch of Taipei City Hospital, Taiwan.
authors.forename: Chun-Teng
authors.initials: CT
authors.lastname: Huang
authors.affiliation: Department of Surgery, Taipei Veterans General Hospital, Taiwan.
authors.forename: Wan-Lun
authors.initials: WL
authors.lastname: Wang
authors.affiliation: Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taiwan.
authors.forename: Chia-Han
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taiwan.
authors.forename: Ka-Yi
authors.initials: KY
authors.lastname: Lau
authors.affiliation: Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taiwan.
authors.forename: Wen-Chun
authors.initials: WC
authors.lastname: Tsai
authors.affiliation: Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taiwan.
authors.forename: Hsiu-Ping
authors.initials: HP
authors.lastname: Yang
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Shiau
authors.affiliation: Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taiwan.|School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Department of Surgery, Taipei Veterans General Hospital, Taiwan.
authors.forename: Ling-Ming
authors.initials: LM
authors.lastname: Tseng
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.|National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Kuen-Feng
authors.identifier: 0000-0002-4686-7019
authors.initials: KF
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001940:Breast / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008819:Mice, Nude; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D043823:Taxoids / Q000494:pharmacology / Q000627:therapeutic use*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D050796:STAT3 Transcription Factor; D043823:Taxoids; D000077143:Docetaxel; D009536:Niacinamide; D000077157:Sorafenib; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse
keywords: SHP-1 agonist; STAT3; triple-negative breast cancer