Journal
CANCER RESEARCH
Volume 68, Issue 5, Pages 1462-1470Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-07-3094
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Funding
- NATIONAL CANCER INSTITUTE [R01CA095519, R01CA114039] Funding Source: NIH RePORTER
- NCI NIH HHS [R01 CA114039, R01 CA114039-04, CA095519, R01 CA095519, CA114039, R01 CA095519-06] Funding Source: Medline
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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-kappa B (NF-kappa B) 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 kappa B 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-kappa B. Expression of a truncated TAB1 mutant [i.e., TAB1(411)] reduced basal and TGF-beta-mediated NF-kappa B 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 TAKI and NF-kappa B. Moreover, small interfering RNA-mediated TAKI 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-kappa B in regulating innate immunity by TGF-beta. Collectively, our findings have defined a novel TAB1:TAK1:IKK beta:NF-kappa B signaling axis that forms aberrantly in breast cancer cells and, consequently, enables oncogenic signaling by TGF-beta.
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