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Aurora-A Regulation of Nuclear Factor-B Signaling by Phosphorylation of IB

¹ The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom and ² Centre for Cancer Therapeutics, The Institute of Cancer Research, Cancer Research UK, Belmont, Surrey, United Kingdom

Requests for reprints: Spiros Linardopoulos, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, United Kingdom. Phone: 44-207-153-5341; Fax: 44-207-153-5340; E-mail: spiros.linardopoulos{at}icr.ac.uk.

The Aurora-A/STK15 gene encodes a kinase that is frequently amplified in cancer. Overexpression of Aurora-A in mammalian cells leads to centrosome amplification, genetic instability, and transformation. In this study, we show that Aurora-A activates nuclear factor-B (NF-B) via IB phosphorylation. Inhibition of endogenous Aurora-A reduces tumor necrosis factor (TNF)–induced IB degradation. We analyzed primary human breast cancers, and 13.6% of samples showed Aurora-A gene amplification, all of which exhibited nuclear localization of NF-B. We propose that this subgroup of patients with breast cancer might benefit from inhibiting Aurora-A. We also show that down-regulation of NF-B via Aurora-A depletion can enhance cisplatin-dependent apoptosis. These data define a new role for Aurora-A in regulating IB that is critical for the activation of NF-B–directed gene expression and may be partially responsible for the oncogenic effect of Aurora-A when the gene is amplified and overexpressed in human tumors. [Cancer Res 2007;67(4):1689–95]

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