Abstract
The membrane bound receptor tyrosine kinase Her2 is overexpressed in approximately 30% of human breast cancers, which correlates with poor prognosis. Her2-induced signaling pathways include MAPK and PI3K/Akt, of which the latter has been shown to be critical for Her2+ breast cancer cell growth and survival. In addition, the NF-κB pathway has been shown to be activated downstream of Her2 overexpression; however, the mechanisms leading to this activation are not currently clear. Using Her2+/ER− breast cancer cells, we show that Her2 activates NF-κB through the canonical pathway which, surprisingly, involves IKKα. Knockdown of IKKα led to a significant decrease in transcription levels of multiple NF-κB-regulated cytokine and chemokine genes. siRNA-mediated knockdown of IKKα resulted in a decrease in cancer cell invasion, but had no effect on cell proliferation. Inhibition of the PI3K/Akt pathway had no effect on NF-κB activation, but significantly inhibited cell proliferation. Our study suggests different roles for the NF-κB and PI3K pathways downstream of Her2, leading to changes in invasion and proliferation of breast cancer cells. In addition this work indicates the importance of IKKα as a mediator of Her2-induced tumor progression.
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Acknowledgements
We thank William Comb for his assistance in the preparation of this paper, as well as Dr H Shelton Earp and Dr Carolyn Sartor for generously providing reagents. This work is funded by NIH RO1CA73756 and RO1CA75080, and Department of Defense Grant BC074027. Support is also provided by the Samuel Waxman Cancer Research Foundation.
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Merkhofer, E., Cogswell, P. & Baldwin, A. Her2 activates NF-κB and induces invasion through the canonical pathway involving IKKα. Oncogene 29, 1238–1248 (2010). https://doi.org/10.1038/onc.2009.410
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DOI: https://doi.org/10.1038/onc.2009.410
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