title: Altered TAB1:I kappaB kinase interaction promotes transforming growth factor beta-mediated nuclear factor-kappaB activation during breast cancer progression.
abstract: The conversion of transforming growth factor beta (TGF-beta) from a tumor suppressor to a tumor promoter occurs frequently during mammary tumorigenesis, yet the molecular mechanisms underlying this phenomenon remain undefined. We show herein that TGF-beta repressed nuclear factor-kappaB (NF-kappaB) activity in normal NMuMG cells, but activated this transcription factor in their malignant counterparts, 4T1 cells, by inducing assembly of TGF-beta-activated kinase 1 (TAK1)-binding protein 1 (TAB1):I kappaB kinase beta (IKK beta) complexes, which led to the stimulation of a TAK1:IKK beta:p65 pathway. TAB1:IKK beta complexes could only be detected in NMuMG cells following their induction of epithelial-mesenchymal transition (EMT), which, on TGF-beta treatment, activated NF-kappaB. Expression of a truncated TAB1 mutant [i.e., TAB1(411)] reduced basal and TGF-beta-mediated NF-kappaB activation in NMuMG cells driven to undergo EMT by TGF-beta and in 4T1 cells stimulated by TGF-beta. TAB1(411) expression also inhibited TGF-beta-stimulated tumor necrosis factor-alpha and cyclooxygenase-2 expression in 4T1 cells. Additionally, the ability of human MCF10A-CA1a breast cancer cells to undergo invasion in response to TGF-beta absolutely required the activities of TAK1 and NF-kappaB. Moreover, small interfering RNA-mediated TAK1 deficiency restored the cytostatic activity of TGF-beta in MCF10A-CA1a cells. Finally, expression of truncated TAB1(411) dramatically reduced the growth of 4T1 breast cancers in syngeneic BALB/c, as well as in nude mice, suggesting a potentially important role of NF-kappaB in regulating innate immunity by TGF-beta. Collectively, our findings have defined a novel TAB1:TAK1:IKK beta:NF-kappaB signaling axis that forms aberrantly in breast cancer cells and, consequently, enables oncogenic signaling by TGF-beta.
authors.affiliation: Department of Pharmacology, University of Colorado Health Sciences Center, Aurora, CO 80045, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Neil
authors.forename: William P
authors.initials: WP
authors.lastname: Schiemann
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis*; D000818:Animals; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D007113:Immunity, Innate; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C099510:TAB1 protein, MAPKKK activator, vertebrate; C486300:TAB1 protein, human; D016212:Transforming Growth Factor beta; D051550:I-kappa B Kinase