title: Targeting of TGF-β-activated protein kinase 1 inhibits chemokine (C-C motif) receptor 7 expression, tumor growth and metastasis in breast cancer.
abstract: TGF-β-activated protein kinase 1 (TAK1) is a critical mediator in inflammation, immune response and cancer development. Our previous study demonstrated that activation of TAK1 increases the expression of chemokine (C-C motif) receptor 7 (CCR7) and promotes lymphatic invasion ability of breast cancer cells. However, the expression and association of activated TAK1 and CCR7 in breast tumor tissues is unknown and the therapeutic effect by targeting TAK1 is also unclear. We showed that activated TAK1 (as indicated by phospho-TAK1) and its binding protein TAB1 are strongly expressed in breast tumor tissues (77% and 74% respectively). In addition, increase of phospho-TAK1 or TAB1 is strongly associated with overexpression of CCR7. TAK1 inhibitor 5Z-7-Oxozeaenol (5Z-O) inhibited TAK1 activity, suppressed downstream signaling pathways including p38, IκB kinase (IKK) and c-Jun N-terminal kinase (JNK) and reduced CCR7 expression in metastatic MDA-MB-231 cells. In addition, 5Z-O repressed NF-κB- and c-JUN-mediated transcription of CCR7 gene. Knockdown of TAB1 attenuated CCR7 expression and tumor growth in an orthotopic animal study. More importantly, lymphatic invasion and lung metastasis were suppressed. Collectively, our results demonstrate that constitutive activation of TAK1 is frequently found in human breast cancer and this kinase is a potential therapeutic target for this cancer.
authors.affiliation: Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan, Republic of China.
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Huang
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan, Republic of China.
authors.forename: Chi-Hsiang
authors.initials: CH
authors.lastname: Chiang
authors.affiliation: Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan, Republic of China.|National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan, Republic of China.|Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan, Republic of China.
authors.forename: Wen-Chun
authors.initials: WC
authors.lastname: Hung
authors.affiliation: Department of Surgery, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, Republic of China.Department of Surgery, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 801, Taiwan, Republic of China.Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan, Republic of China.|Department of Surgery, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, Republic of China.Department of Surgery, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 801, Taiwan, Republic of China.Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan, Republic of China.|Department of Surgery, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, Republic of China.Department of Surgery, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 801, Taiwan, Republic of China.Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan, Republic of China.
authors.forename: Ming-Feng
authors.initials: MF
authors.lastname: Hou
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D054415:Chemokine CCL19 / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008875:Middle Aged; D009362:Neoplasm Metastasis; D034622:RNA Interference; D054400:Receptors, CCR7 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D047368:Tumor Burden / Q000235:genetics; D023041:Xenograft Model Antitumor Assays / Q000379:methods*; D015025:Zearalenone / Q000031:analogs & derivatives / Q000494:pharmacology / Q000008:administration & dosage; D000099151:MAP Kinase Kinase Kinase 7; D007783:Lactones; D012118:Resorcinols
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D054415:Chemokine CCL19; D020930:MAP Kinase Kinase Kinases; D054400:Receptors, CCR7; D015025:Zearalenone; D000099151:MAP Kinase Kinase Kinase 7; C505734:7-oxozeanol; D007783:Lactones; D012118:Resorcinols; C515370:CCR7 protein, human; C486300:TAB1 protein, human