Abstract
Inflammation enhances tumour promotion through NF-κB-dependent mechanisms. NF-κB was also proposed to promote metastatogenesis through epithelial-mesenchymal transition. Yet a mechanistic link between inflammation and metastasis is missing. We identified a role for IκB kinase α (IKKα), activated by receptor activator of NF-κB (RANK/TNFRSF11A), in mammary epithelial proliferation during pregnancy. Owing to similarities between mammary and prostate epithelia, we examined IKKα involvement in prostate cancer and its progression. Here we show that a mutation that prevents IKKα activation slows down CaP growth and inhibits metastatogenesis in TRAMP mice, which express SV40 T antigen in the prostate epithelium. Decreased metastasis correlated with elevated expression of the metastasis suppressor Maspin, the ablation of which restored metastatic activity. IKKα activation by RANK ligand (RANKL/TNFSF11) inhibits Maspin expression in prostate epithelial cells, whereas repression of Maspin transcription requires nuclear translocation of active IKKα. The amount of active nuclear IKKα in mouse and human prostate cancer correlates with metastatic progression, reduced Maspin expression and infiltration of prostate tumours with RANKL-expressing inflammatory cells. We propose that tumour-infiltrating RANKL-expressing cells lead to nuclear IKKα activation and inhibition of Maspin transcription, thereby promoting the metastatic phenotype.
Original language | English (US) |
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Pages (from-to) | 690-694 |
Number of pages | 5 |
Journal | Nature |
Volume | 446 |
Issue number | 7136 |
DOIs | |
State | Published - Apr 5 2007 |
Funding
Acknowledgements J.-L.L. was supported by the Aventis-UICC Translational Cancer Research Fellowship, the Lopiccola Fellowship of the UCSD Cancer Center and the Life Science Research Fellowship. W.T. was supported by a postdoctoral fellowship from The Susan G. Komen Breast Cancer Foundation. Work in M.K.’s laboratory was supported by grants from the NIH, the US Army Medical Research and Materiel Command and the Prostate Cancer Foundation. M.K. is an American Cancer Society Research Professor. We thank M. Stampfer for HME cells, S. Srivastava and Z. Khalkhali-Ellis for Maspin–luciferase reporters and H. R. Li for assistance with the statistical analysis.
ASJC Scopus subject areas
- General