Abstract
The tumor-promoting arm of transforming growth factor beta (TGF-β) receptor signaling contributes to advanced cancer progression and is considered a master regulator of breast cancer metastasis. In mammals, there are six distinct members in the tumor-necrosis factor receptor (TNFR)-associated factor (TRAF) family (TRAF1-TRAF6), with the function of TRAF4 not being extensively studied in the past decade. Although numerous studies have suggested that there is elevated TRAF4 expression in human cancer, it is still unknown in which oncogenic pathway TRAF4 is mainly implicated. This review highlights TGF-β-induced SMAD-dependent signaling and non-SMAD signaling as the major pathways regulated by TRAF4 involved in breast cancer metastasis.
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Zhang L, Huang H, Zhou F, Schimmel J, Pardo CG, Zhang T, Barakat TS, Sheppard KA, Mickanin C, Porter JA, Vertegaal AC, van Dam H, Gribnau J, Lu CX, ten Dijke P. Mol Cell, 2012, 46: 650–661
Zhang L, Zhou F, Drabsch Y, Gao R, Snaar-Jagalska BE, Mickanin C, Huang H, Sheppard KA, Porter JA, Lu CX, ten Dijke P. Nat Cell Biol, 2012, 14: 717–726
Zhang L, Zhou F, Garcia de Vinuesa A, de Kruijf EM, Mesker WE, Hui L, Drabsch Y, Li Y, Bauer A, Rousseau A, Sheppard KA, Mickanin C, Kuppen PJ, Lu CX, Ten Dijke P. Mol Cell, 2013, 51: 559–572
Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol, 2003, 3: 745–756
Ha H, Han D, Choi Y. TRAF-mediated TNFR-family signaling. Curr Protoc Immunol, 2009, 87: 11.9D.1–11.9D.19
Chung JY, Park YC, Ye H, Wu H. All TRAFs are not created equal: common and distinct molecular mechanisms of TRAF-mediated signal transduction. J Cell Sci, 2002, 115: 679–688
Kedinger V, Rio M C. TRAF4, the unique family member. Adv Exp Med Biol, 2007, 597: 60–71
Regnier CH, Masson R, Kedinger V, Textoris J, Stoll I, Chenard MP, Dierich A, Tomasetto C, Rio MC. Impaired neural tube closure, axial skeleton malformations, and tracheal ring disruption in TRAF4-deficient mice. Proc Natl Acad Sci USA, 2002, 99: 5585–5590
Shiels H, Li X, Schumacker PT, Maltepe E, Padrid PA, Sperling A, Thompson CB, Lindsten T. TRAF4 deficiency leads to tracheal malformation with resulting alterations in air flow to the lungs. Am J Pathol, 2000, 157: 679–688
Regnier CH, Tomasetto C, Moog-Lutz C, Chenard MP, Wendling C, Basset P, Rio MC. Presence of a new conserved domain in CART1, a novel member of the tumor necrosis factor receptorassociated protein family, which is expressed in breast carcinoma. J Biol Chem, 1995, 270: 25715–25721
Camilleri-Broet S, Cremer I, Marmey B, Comperat E, Viguie F, Audouin J, Rio MC, Fridman WH, Sautes-Fridman C, Regnier CH. TRAF4 overexpression is a common characteristic of human carcinomas. Oncogene, 2007, 26: 142–147
Bieche I, Tomasetto C, Regnier CH, Moog-Lutz C, Rio MC, Lidereau R. Two distinct amplified regions at 17q11-q21 involved in human primary breast cancer. Cancer Res, 1996, 56: 3886–3890
Moustakas A, Heldin C H. The regulation of TGFβ signal transduction. Development, 2009, 136: 3699–3714
Kang J S, Liu C, Derynck R. New regulatory mechanisms of TGF-β receptor function. Trends Cell Biol, 2009, 19: 385–394
Ikushima H, Miyazono K. TGFβ signalling: a complex web in cancer progression. Nat Rev Cancer, 2010, 10: 415–424
Massague J. TGFβ in cancer. Cell, 2008, 134: 215–230
Zhang L, Zhou F, ten Dijke P. Signaling interplay between transforming growth factor-β receptor and PI3K/AKT pathways in cancer. Trends Biochem Sci, 2013, 38: 612–620
Xu J, Lamouille S, Derynck R. TGF-β-induced epithelial to mesenchymal transition. Cell Res, 2009, 19: 156–172
Zhang Y E. Non-Smad pathways in TGF-β signaling. Cell Res, 2009, 19: 128–139
Mu Y, Gudey S K, Landstrom M. Non-Smad signaling pathways. Cell Tissue Res, 2012, 347: 11–20
Yang, YA, Dukhanina O, Tang B, Mamura M, Letterio JJ, Mac-Gregor J, Patel SC, Khozin S, Liu ZY, Green J, Anver MR, Merlino G, Wakefield LM. Lifetime exposure to a soluble TGF-β antagonist protects mice against metastasis without adverse side effects. J Clin Invest, 2002, 109: 1607–1615
Muraoka RS, Dumont N, Ritter CA, Dugger TC, Brantley DM, Chen J, Easterly E, Roebuck LR, Ryan S, Gotwals PJ, Koteliansky V, Arteaga CL. Blockade of TGF-β inhibits mammary tumor cell viability, migration, and metastases. J Clin Invest, 2002, 109: 1551–1559
Bandyopadhyay A, Lopez-Casillas F, Malik SN, Montiel JL, Mendoza V, Yang J, Sun LZ. Antitumor activity of a recombinant soluble betaglycan in human breast cancer xenograft. Cancer Res, 2002, 62: 4690–4695
Hu Z, Zhang Z, Guise T, Seth P. Systemic delivery of an oncolytic adenovirus expressing soluble transforming growth factor-β receptor II-Fc fusion protein can inhibit breast cancer bone metastasis in a mouse model. Hum Gene Ther, 2010, 21: 1623–1629
Bandyopadhyay A, Agyin JK, Wang L, Tang Y, Lei X, Story BM, Cornell JE, Pollock BH, Mundy GR, Sun LZ. Inhibition of pulmonary and skeletal metastasis by a transforming growth factor-β type I receptor kinase inhibitor. Cancer Res, 2006, 66: 6714–6721
Korpal M, Yan J, Lu X, Xu S, Lerit DA, Kang Y. Imaging transforming growth factor-beta signaling dynamics and therapeutic response in breast cancer bone metastasis. Nat Med, 2009, 15: 960–966
Seoane J. Imaging transforming growth factor-β signaling dynamics and therapeutic response in breast cancer bone metastasis. Clin Transl Oncol, 2008, 10: 14–19
Akhurst R J, Hata A. Targeting the TGFβ signalling pathway in disease. Nat Rev Drug Discov, 2012, 11: 790–811
Kavsak P, Rasmussen RK, Causing CG, Bonni S, Zhu H, Thomsen GH, Wrana JL. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGFβ receptor for degradation. Mol Cell, 2000, 6: 1365–1375
Eichhorn PJ, Rodon L, Gonzalez-Junca A, Dirac A, Gili M, Martinez-Saez E, Aura C, Barba I, Peg V, Prat A, Cuartas I, Jimenez J, Garcia-Dorado D, Sahuquillo J, Bernards R, Baselga J, Seoane J. USP15 stabilizes TGF-β receptor I and promotes oncogenesis through the activation of TGF-β signaling in glioblastoma. Nat Med, 2012, 18: 429–435
Moustakas A, Heldin C H. Coordination of TGF-β signaling by ubiquitylation. Mol Cell, 2013, 51: 555–556
Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature, 2001, 412: 346–351
Xia ZP, Sun L, Chen X, Pineda G, Jiang X, Adhikari A, Zeng W, Chen ZJ. Direct activation of protein kinases by unanchored polyubiquitin chains. Nature, 2009, 461: 114–119
Sorrentino A, Thakur N, Grimsby S, Marcusson A, von Bulow V, Schuster N, Zhang S, Heldin CH, Landstrom M. The type I TGF-β receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner. Nat Cell Biol, 2008, 10: 1199–1207
Yamashita M, Fatyol K, Jin C, Wang X, Liu Z, Zhang YE. TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-β. Mol Cell, 2008, 31: 918–924
Friedl P, Alexander S. Cancer invasion and the microenvironment: plasticity and reciprocity. Cell, 2011, 147: 992–1009
Kang Y, Pantel K. Tumor cell dissemination: emerging biological insights from animal models and cancer patients. Cancer Cell, 2013, 23: 573–581
Wang X, Jin C, Tang Y, Tang L Y, Zhang YE. Ubiquitination of tumor necrosis factor receptor-associated factor 4 (TRAF4) by Smad ubiquitination regulatory factor 1 (Smurf1) regulates motility of breast epithelial and cancer cells. J Biol Chem, 2013, 288: 21784–21792
Rousseau A, McEwen AG, Poussin-Courmontagne P, Rognan D, Nomine Y, Rio MC, Tomasetto C, Alpy F. TRAF4 is a novel phosphoinositide-binding protein modulating tight junctions and favoring cell migration. PLoS Biol, 2013, 11: e1001726
Ur-Rehman S, Gao Q, Mitsopoulos C, Zvelebil M. ROCK: a resource for integrative breast cancer data analysis. Breast Cancer Res Treat, 2013, 139: 907–921
Loi S, Haibe-Kains B, Desmedt C, Wirapati P, Lallemand F, Tutt AM, Gillet C, Ellis P, Ryder K, Reid JF, Daidone MG, Pierotti MA, Berns EM, Jansen MP, Foekens JA, Delorenzi M, Bontempi G, Piccart MJ, Sotiriou C. Predicting prognosis using molecular profiling in estrogen receptor-positive breast cancer treated with tamoxifen. BMC Genomics, 2008, 9: 239
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Zhou, F., Li, F., Xie, F. et al. TRAF4 mediates activation of TGF-β signaling and is a biomarker for oncogenesis in breast cancer. Sci. China Life Sci. 57, 1172–1176 (2014). https://doi.org/10.1007/s11427-014-4727-x
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DOI: https://doi.org/10.1007/s11427-014-4727-x