The role of the NF-kappaB pathway in Her2-overexpressing breast cancer

Overexpression of the membrane-bound receptor tyrosine kinase Her2 (ErbB-2, EGFR2) occurs in approximately 30% of all breast cancers and typically correlates with poor prognosis. Overexpression of Her2 leads to activation of multiple downstream pathways including the MAPK, PI3K/Akt and NF-κB pathways. Her2 has been previously reported to activate the NF-κB pathway. However, the mechanism by which this occurs is poorly elucidated. In this report, we utilize an siRNA approach to investigate the role that the different Inhibitor of Kappa-B Kinase (IKK) subunits play in activation of NF-κB downstream of Her2. We show that IKKα plays a previously unreported role in NF-κB activation via the canonical pathway in Her2-overexpressing breast cancer cells. Furthermore, IKKα plays an important role in NF-κB regulated gene expression and induction of an invasive phenotype in these cells, independent of PI3K. This activation of NF-κB by Her2 also requires the NF-κB pathway kinase, TGF-β-activated kinase 1 (TAK1). Finally, we also show that inhibition of IKKα by siRNA leads to activation of SPARC, a member of the BM-40 family of genes which are often dysregulated in cancer. Activation of the NF-κB pathway can directly suppress expression of SPARC through a mechanism at the promoter of SPARC, proximal to the transcriptional start site. In summary, we present data elucidating the role and consequences of NF-κB activation in Her2-overexpressing breast cancer.