Her2 activates NF-κB and induces invasion through the canonical pathway involving IKKα

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-kappa B 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-kappa B through the canonical pathway which, surprisingly, involves IKK alpha. Knockdown of IKK alpha led to a significant decrease in transcription levels of multiple NF-kappa B-regulated cytokine and chemokine genes. siRNA-mediated knockdown of IKK alpha 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-kappa B activation, but significantly inhibited cell proliferation. Our study suggests different roles for the NF-kappa B 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 IKK alpha as a mediator of Her2-induced tumor progression. Oncogene ( 2010) 29, 1238-1248; doi: 10.1038/onc.2009.410; published online 30 November 2009