title: Extracellular Visfatin-Promoted Malignant Behavior in Breast Cancer Is Mediated Through c-Abl and STAT3 Activation.
abstract: OBJECTIVE
  Visfatin is an adipocytokine involved in cellular metabolism, inflammation, and cancer. This study investigated the roles of extracellular visfatin in breast cancer, and explored underlying mechanisms in clinical and experimental settings.
  
  
  METHODS
  Associations of serum visfatin with clinicopathologic characteristics and patient survival were assessed with Cox regression models and Kaplan-Meier analyses. Effects of extracellular visfatin on cultured breast cancer cells were examined, followed by in vivo investigation of tumor growth and metastasis in xenograft animal models. Imatinib and Stattic were used to inhibit c-Abl and STAT3 activation, respectively.
  
  
  RESULTS
  Breast cancer patients with high serum visfatin levels were associated with advanced tumor stage, increased tumor size and lymph node metastasis, and poor survival. Elevated phosphorylation of c-Abl and STAT3 in breast tumor tissues were correlated with high serum visfatin levels in patients. Visfatin-promoted in vitro cell viability and metastatic capability were suppressed by imatinib (c-Abl inhibitor) and Stattic (STAT3 inhibitor). Increased in vivo cell invasiveness was observed in zebrafish xenografted with visfatin-pretreated breast cancer cells. Tumor growth and lung metastasis occurred in visfatin-administered mice xenografted with breast cancer cells. Tail vein-injected mice with visfatin-pretreated breast cancer cells showed increased lung metastasis, which was suppressed by imatinib.
  
  
  CONCLUSIONS
  Serum visfatin levels in breast cancer patients reveal potential prognostic values, and our findings that visfatin promoted breast cancer through activation of c-Abl and STAT3 may provide an important molecular basis for future design of targeted therapies that take into account different serum visfatin levels in breast cancer. Clin Cancer Res; 22(17); 4478-90. ©2016 AACR.
authors.affiliation: Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Amos C
authors.initials: AC
authors.lastname: Hung
authors.affiliation: Canniesburn Plastic Surgery Unit, Royal Infirmary, Glasgow, Scotland, United Kingdom.
authors.forename: Steven
authors.initials: S
authors.lastname: Lo
authors.affiliation: Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Ming-Feng
authors.initials: MF
authors.lastname: Hou
authors.affiliation: Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan. Department of Anatomy, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yi-Chen
authors.initials: YC
authors.lastname: Lee
authors.affiliation: Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chun-Hao
authors.initials: CH
authors.lastname: Tsai
authors.affiliation: Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yuan-Yin
authors.initials: YY
authors.lastname: Chen
authors.affiliation: Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Wangta
authors.initials: W
authors.lastname: Liu
authors.affiliation: Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yu-Han
authors.initials: YH
authors.lastname: Su
authors.affiliation: Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yi-Hsuan
authors.initials: YH
authors.lastname: Lo
authors.affiliation: Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chie-Hong
authors.initials: CH
authors.lastname: Wang
authors.affiliation: Department of Biological Science and Technology and Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, Taiwan.
authors.forename: Shiou-Chen
authors.initials: SC
authors.lastname: Wu
authors.affiliation: Department of Medical Research, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan.
authors.forename: Ya-Ching
authors.initials: YC
authors.lastname: Hsieh
authors.affiliation: Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Stephen Chu-Sung
authors.initials: SC
authors.lastname: Hu
authors.affiliation: Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
authors.forename: Ming-Hong
authors.initials: MH
authors.lastname: Tai
authors.affiliation: Department of Biological Science and Technology and Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, Taiwan. yuanssf@ms33.hinet.net ymwang@mail.nctu.edu.tw.
authors.forename: Yun-Ming
authors.initials: YM
authors.lastname: Wang
authors.affiliation: Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan. Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan. yuanssf@ms33.hinet.net ymwang@mail.nctu.edu.tw.
authors.forename: Shyng-Shiou F
authors.initials: SS
authors.lastname: Yuan
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D015415:Biomarkers; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D054409:Nicotinamide Phosphoribosyltransferase / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D011379:Prognosis; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D015415:Biomarkers; D014408:Biomarkers, Tumor; D050796:STAT3 Transcription Factor; D054409:Nicotinamide Phosphoribosyltransferase; D016315:Proto-Oncogene Proteins c-abl