1. Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Cancer Center, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0723, USA
2. Department of Pathology and the Moores Cancer Center, University of California, San Diego, La Jolla, California 92093-0803, USA
3. Baylor College of Medicine, Department of Molecular and Cellular Biology, One Baylor Plaza, Houston, Texas 77030, USA

Correspondence to: Michael Karin¹ Correspondence and requests for materials should be addressed to M.K. (Email: karinoffice@ucsd.edu).

Abstract

Inflammation enhances tumour promotion through NF-B-dependent mechanisms¹. NF-B was also proposed to promote metastatogenesis through epithelial–mesenchymal transition². Yet a mechanistic link between inflammation and metastasis is missing. We identified a role for IB kinase (IKK), activated by receptor activator of NF-B (RANK/TNFRSF11A), in mammary epithelial proliferation during pregnancy³. Owing to similarities between mammary and prostate epithelia, we examined IKK involvement in prostate cancer and its progression. Here we show that a mutation that prevents IKK activation slows down CaP growth and inhibits metastatogenesis in TRAMP mice, which express SV40 T antigen in the prostate epithelium⁴. Decreased metastasis correlated with elevated expression of the metastasis suppressor Maspin⁵, the ablation of which restored metastatic activity. IKK activation by RANK ligand (RANKL/TNFSF11) inhibits Maspin expression in prostate epithelial cells, whereas repression of Maspin transcription requires nuclear translocation of active IKK. The amount of active nuclear IKK 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 IKK activation and inhibition of Maspin transcription, thereby promoting the metastatic phenotype.

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