TAK1–TAB2 Signaling Contributes to Bone Destruction by Breast Carcinoma Cells

Advanced-stage breast cancers frequently metastasize to the bones and cause bone destruction, but the underlying mechanism is not fully understood. This study presents evidence that TGF-β–activated protein kinase 1 (TAK1) signaling in tumor cells promotes bone destruction by metastatic breast carcinoma cells, controlling expression of prometastatic factors including matrix metalloproteinase (MMP) 9 and COX2. Suppression of TAK1 signaling by dominant-negative TAK1 (dn-TAK1) in breast carcinoma MDA-MB-231 cells impairs bone colonization by carcinoma cells and bone osteolysis in the intracardiac injection model. Mechanistic studies showed that inhibition of TAK1 by dn-TAK1 or siRNA blocked expression of factors implicated in bone metastasis, such as MMP-9, COX2/PTGS2, parathyroid hormone–related protein (PTHrP) and interleukin 8 (IL-8), but did not affect activation of p38MAPK by TGF-β. TAK1 signaling is mediated by TAK1-binding partners TAB1, TAB2, and TAB3. Carcinoma cells express elevated mRNA levels of TAB2 and TAB3, whereas the TAB1 expression is noticeably low. Accordingly, depletion of TAB2 by siRNA reduced expression of MMP-9 and COX2. Together, these studies show that the TAK1–TAB2-TAB3 signaling axis is critical for carcinoma-induced bone lesions, mediating expression of proinvasive and osteolytic factors. These findings identify the TAK1–TAB2 axis as a potential therapeutic target in bone metastasis. Mol Cancer Res; 9(8); 1042–53. ©2011 AACR.

[1]  X. Zhang,et al.  Src is a major signaling component for CTGF induction by TGF‐β1 in osteoblasts , 2010, Journal of cellular physiology.

[2]  I. Bedrosian,et al.  Cyclooxygenase-2 expression in primary breast cancers predicts dissemination of cancer cells to the bone marrow , 2009, Breast Cancer Research and Treatment.

[3]  J. Ninomiya-Tsuji,et al.  TAK1-binding Protein 1, TAB1, Mediates Osmotic Stress-induced TAK1 Activation but Is Dispensable for TAK1-mediated Cytokine Signaling* , 2008, Journal of Biological Chemistry.

[4]  X. Zhang,et al.  Molecular requirements for induction of CTGF expression by TGF-beta1 in primary osteoblasts. , 2008, Bone.

[5]  P. Cohen,et al.  Roles for TAB1 in regulating the IL-1-dependent phosphorylation of the TAB3 regulatory subunit and activity of the TAK1 complex. , 2008, The Biochemical journal.

[6]  T. Sculco,et al.  Expression profiling reveals alternative macrophage activation and impaired osteogenesis in periprosthetic osteolysis , 2008, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[7]  Andrei V Bakin,et al.  TAK1 is required for TGF-β1-mediated regulation of matrix metalloproteinase-9 and metastasis , 2007, Oncogene.

[8]  J. Lieberman,et al.  Tumor metastasis to bone , 2007, Arthritis research & therapy.

[9]  Zhijian J. Chen,et al.  Ubiquitin-mediated activation of TAK1 and IKK , 2007, Oncogene.

[10]  N. Gebbia,et al.  MMP-2, MMP-9 and activin A blood levels in patients with breast cancer or prostate cancer metastatic to the bone. , 2007, Anticancer research.

[11]  Andrei V Bakin,et al.  ALK5 promotes tumor angiogenesis by upregulating matrix metalloproteinase-9 in tumor cells , 2007, Oncogene.

[12]  T. Giordano,et al.  NF-κB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via GM-CSF , 2007, Nature Medicine.

[13]  C. Schem,et al.  Increased COX2 expression enhances tumor-induced osteoclastic lesions in breast cancer bone metastasis , 2008, Clinical & Experimental Metastasis.

[14]  A. Lipton.  Future Treatment of Bone Metastases , 2006, Clinical Cancer Research.

[15]  P. ten Dijke,et al.  The tumor suppressor Smad4 is required for transforming growth factor beta-induced epithelial to mesenchymal transition and bone metastasis of breast cancer cells. , 2006, Cancer research.

[16]  Michael Karin,et al.  NF-κB: linking inflammation and immunity to cancer development and progression , 2005, Nature Reviews Immunology.

[17]  Sophie Janssens,et al.  Transforming Growth Factor- 1 to the Bone , 2005 .

[18]  Wei He,et al.  Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[19]  S. Akira,et al.  Essential function for the kinase TAK1 in innate and adaptive immune responses , 2005, Nature Immunology.

[20]  E. Vellenga,et al.  Inhibition of the Transforming Growth Factor β (TGFβ) Pathway by Interleukin-1β Is Mediated through TGFβ-activated Kinase 1 Phosphorylation of SMAD3 , 2005 .

[21]  A. Hoffmann,et al.  Transforming Growth Factor-β-activated Kinase-1 (TAK1), a MAP3K, Interacts with Smad Proteins and Interferes with Osteogenesis in Murine Mesenchymal Progenitors*[boxs] , 2005, Journal of Biological Chemistry.

[22]  Fang Liu,et al.  Signaling mechanism of TGF-beta1 in prevention of renal inflammation: role of Smad7. , 2005, Journal of the American Society of Nephrology : JASN.

[23]  E. Schwarz,et al.  Nuclear factor-kappaB-dependent mechanisms in breast cancer cells regulate tumor burden and osteolysis in bone. , 2005, Cancer research.

[24]  T. Guise,et al.  Breast Cancer Metastasis to Bone: Mechanisms of Osteolysis and Implications for Therapy , 2005, Journal of Mammary Gland Biology and Neoplasia.

[25]  T. Yoneda,et al.  Crosstalk between cancer cells and bone microenvironment in bone metastasis. , 2005, Biochemical and biophysical research communications.

[26]  H. Sakurai,et al.  Critical Roles of Threonine 187 Phosphorylation in Cellular Stress-induced Rapid and Transient Activation of Transforming Growth Factor-β-activated Kinase 1 (TAK1) in a Signaling Complex Containing TAK1-binding Protein TAB1 and TAB2* , 2005, Journal of Biological Chemistry.

[27]  Carlos L Arteaga,et al.  Dual role of transforming growth factor beta in mammary tumorigenesis and metastatic progression. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[28]  E. Vellenga,et al.  Inhibition of the transforming growth factor beta (TGFbeta) pathway by interleukin-1beta is mediated through TGFbeta-activated kinase 1 phosphorylation of SMAD3. , 2005, Molecular biology of the cell.

[29]  S. Groshen,et al.  Stromal Matrix Metalloproteinase-9 Regulates the Vascular Architecture in Neuroblastoma by Promoting Pericyte Recruitment , 2004, Cancer Research.

[30]  Z. Werb,et al.  Matrix remodeling during endochondral ossification. , 2004, Trends in cell biology.

[31]  E. Rosenthal,et al.  Breast cancer cells with inhibition of p38α have decreased MMP-9 activity and exhibit decreased bone metastasis in mice , 2004, Clinical & Experimental Metastasis.

[32]  R. Gaynor,et al.  Role of the TAB2‐related protein TAB3 in IL‐1 and TNF signaling , 2003, The EMBO journal.

[33]  L. Wakefield,et al.  The two faces of transforming growth factor β in carcinogenesis , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[34]  C. Cordon-Cardo,et al.  A multigenic program mediating breast cancer metastasis to bone. , 2003, Cancer cell.

[35]  C. Arteaga,et al.  Autocrine Transforming Growth Factor-β Signaling Mediates Smad-independent Motility in Human Cancer Cells* , 2003, The Journal of Biological Chemistry.

[36]  S. Thorgeirsson,et al.  Transient activation of NF-κB through a TAK1/IKK kinase pathway by TGF-β1 inhibits AP-1/SMAD signaling and apoptosis: implications in liver tumor formation , 2003, Oncogene.

[37]  E. Wagner,et al.  A Central Role for the JNK Pathway in Mediating the Antagonistic Activity of Pro-inflammatory Cytokines against Transforming Growth Factor-β-driven SMAD3/4-specific Gene Expression* , 2003, The Journal of Biological Chemistry.

[38]  L. Wakefield,et al.  The two faces of transforming growth factor beta in carcinogenesis. , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[39]  R. Derynck,et al.  Smad-dependent and Smad-independent pathways in TGF-beta family signalling. , 2003, Nature.

[40]  C. Arteaga,et al.  p38 mitogen-activated protein kinase is required for TGFbeta-mediated fibroblastic transdifferentiation and cell migration. , 2002, Journal of cell science.

[41]  J. Chirgwin,et al.  Transforming Growth Factor-Stimulates Parathyroid Hormone-related Protein and Osteolytic Metastases via Smad and Mitogen-activated Protein Kinase Signaling Pathways * , 2002 .

[42]  M. Rizzo,et al.  Phosphatidylinositol 3-Kinase and NF-κB Regulate Motility of Invasive MDA-MB-231 Human Breast Cancer Cells by the Secretion of Urokinase-type Plasminogen Activator* , 2002, The Journal of Biological Chemistry.

[43]  N. Sakurai,et al.  Receptor activator of NF-kappaB ligand (RANKL) activates TAK1 mitogen-activated protein kinase kinase kinase through a signaling complex containing RANK, TAB2, and TRAF6. , 2002, Molecular and cellular biology.

[44]  F. Orr,et al.  The effect of Neovastat (AE-941) on an experimental metastatic bone tumor model. , 2002, International journal of oncology.

[45]  J. Chirgwin,et al.  Transforming growth factor-beta stimulates parathyroid hormone-related protein and osteolytic metastases via Smad and mitogen-activated protein kinase signaling pathways. , 2002, The Journal of biological chemistry.

[46]  H. Moses,et al.  Integrin (cid:1) 1 Signaling Is Necessary for Transforming Growth Factor- (cid:1) Activation of p38MAPK and Epithelial Plasticity* , 2022 .

[47]  H. Ogata,et al.  Human breast cancer MDA-MB-231 cells fail to express the neurofibromin protein, lack its type I mRNA isoform and show accumulation of P-MAPK and activated Ras. , 2001, Cancer letters.

[48]  R. Beauchamp,et al.  Oncogenic Ras Represses Transforming Growth Factor-β/Smad Signaling by Degrading Tumor Suppressor Smad4* , 2001, The Journal of Biological Chemistry.

[49]  Stephanie Birkey Reffey,et al.  X-linked Inhibitor of Apoptosis Protein Functions as a Cofactor in Transforming Growth Factor-β Signaling* , 2001, The Journal of Biological Chemistry.

[50]  H. Moses,et al.  Integrin beta 1 signaling is necessary for transforming growth factor-beta activation of p38MAPK and epithelial plasticity. , 2001, The Journal of biological chemistry.

[51]  P. Watson,et al.  A matrix metalloproteinase inhibitor, batimastat, retards the development of osteolytic bone metastases by MDA-MB-231 human breast cancer cells in Balb C nu/nu mice. , 2001, European journal of cancer.

[52]  K. Krieglstein,et al.  Targeted mutations of transforming growth factor-beta genes reveal important roles in mouse development and adult homeostasis. , 2000, European journal of biochemistry.

[53]  H. Moses,et al.  Phosphatidylinositol 3-Kinase Function Is Required for Transforming Growth Factor β-mediated Epithelial to Mesenchymal Transition and Cell Migration* , 2000, The Journal of Biological Chemistry.

[54]  Shigeyoshi Itohara,et al.  Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis , 2000, Nature Cell Biology.

[55]  H. Nakshatri,et al.  Repression of transforming-growth-factor-β-mediated transcription by nuclear factor κB , 2000 .

[56]  Paul J. Williams,et al.  Actions of bisphosphonate on bone metastasis in animal models of breast carcinoma , 2000, Cancer.

[57]  K. Irie,et al.  TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway. , 2000, Molecular cell.

[58]  E. Bottinger,et al.  A mechanism of suppression of TGF–β/SMAD signaling by NF-κB/RelA , 2000, Genes & Development.

[59]  H. Nakshatri,et al.  Repression of transforming-growth-factor-beta-mediated transcription by nuclear factor kappaB. , 2000, The Biochemical journal.

[60]  M. Bitzer,et al.  A mechanism of suppression of TGF-beta/SMAD signaling by NF-kappa B/RelA. , 2000, Genes & development.

[61]  Anita B. Roberts,et al.  Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response , 1999, Nature Cell Biology.

[62]  H. Yoshida,et al.  TGF-β1 Inhibits NF-κB Activity through Induction of IκB-α Expression in Human Salivary Gland Cells: A Possible Mechanism of Growth Suppression by TGF-β1 , 1999 .

[63]  W. Toriumi,et al.  Functional Interactions of Transforming Growth Factor β-activated Kinase 1 with IκB Kinases to Stimulate NF-κB Activation* , 1999, The Journal of Biological Chemistry.

[64]  J. Massagué,et al.  A mechanism of repression of TGFbeta/ Smad signaling by oncogenic Ras. , 1999, Genes & development.

[65]  R Wieser,et al.  TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. , 1999, The Journal of clinical investigation.

[66]  Naoto Ueno,et al.  XIAP, a cellular member of the inhibitor of apoptosis protein family, links the receptors to TAB1–TAK1 in the BMP signaling pathway , 1999, The EMBO journal.

[67]  M. Collins,et al.  Matrix metalloproteinase-9 (MMP-9) expression in childhood osseous osteosarcoma. , 1998, Medical and pediatric oncology.

[68]  Gabriele Bergers,et al.  MMP-9/Gelatinase B Is a Key Regulator of Growth Plate Angiogenesis and Apoptosis of Hypertrophic Chondrocytes , 1998, Cell.

[69]  A. Gulino,et al.  Transforming growth factor‐β1 enhances the invasiveness of human MDA‐MB‐231 breast cancer cells by up‐regulating urokinase activity , 1998 .

[70]  K. Irie,et al.  Role of TAK1 and TAB1 in BMP signaling in early Xenopus development , 1998, The EMBO journal.

[71]  J. Massagué.  TGF-beta signal transduction. , 1998, Annual review of biochemistry.

[72]  M. Arsura,et al.  Nuclear factor-kappaB/Rel blocks transforming growth factor beta1-induced apoptosis of murine hepatocyte cell lines. , 1997, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[73]  R. Kind,et al.  The Nature of the 660-Kilometer Upper-Mantle Seismic Discontinuity from Precursors to the PP Phase , 1996, Science.

[74]  B F Boyce,et al.  Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. , 1996, The Journal of clinical investigation.

[75]  K. Irie,et al.  TAB1: An Activator of the TAK1 MAPKKK in TGF-β Signal Transduction , 1996, Science.

[76]  K. Irie,et al.  TAB1: an activator of the TAK1 MAPKKK in TGF-beta signal transduction. , 1996, Science.

[77]  K. Irie,et al.  Identification of a Member of the MAPKKK Family as a Potential Mediator of TGF-β Signal Transduction , 1995, Science.

[78]  B F Boyce,et al.  Bisphosphonate risedronate reduces metastatic human breast cancer burden in bone in nude mice. , 1995, Cancer research.

[79]  R. Furlanetto,et al.  Incidence and distribution of experimental metastases in mutant mice with defective organ microenvironments (genotypes Sl/Sld and W/Wv). , 1992, Cancer research.

[80]  R. Baggs,et al.  A murine model of experimental metastasis to bone and bone marrow. , 1988, Cancer research.

[81]  M. Olivé,et al.  Breast tumor cell lines from pleural effusions. , 1974, Journal of the National Cancer Institute.