NF-κB activation in basal and HER2+ breast cancers occurs via different mechanisms

A35 The NF-κB transcription factor plays an active role in inflammatory response, cellular growth, and apoptosis and is active in several malignant diseases, including cancer. Inhibition of NF-κB is expected to block cell proliferation and tumor formation and thus genes that activate NF-κB are potential drug targets in the treatment of cancer. Our study aims to infer from mRNA gene expression data the status and the mechanism of activation of NF-κB in basal, HER2+ and luminal breast cancer subtypes recently discovered in (Alexe, Dalgin et al, CaRes 2007). Experiments to validate these findings will be conducted and presented in a separate study.
 Activation of NF-κB is known to be initiated via the canonical and the alternative pathways. In the canonical pathway the IκB kinase (IKK) complex activates NF-κB. The non-canonical pathway involves activation of NF-κB by IKKα and NIK. Two other kinases, the IKKϵ (IKBKE) oncogene and TBK1 have also been shown to activate NF-κB.
 Our analysis was performed on three breast cancer gene expression datasets available at GEO (GSE2034, GSE4922 and GSE7390). The presence of the NF-κB activity was evaluated based on up-stream and down-stream events for the canonical and the alternative pathway, and quantified through a consensus of several gene-set enrichment scores (Tamayo et al, PNAS 2005). We found that the upstream oncogene IKBKE and the NF-κB downstream target genes are upregulated only in the basal (BA) tumors and in the HER2+ tumors presenting a lymphocytic infiltrate (HER2+I). Two isoforms (AKT2 and AKT3) of the AKT kinase which activate NF-κB via the alternative pathway are overexpressed in BA, while another isoform (AKT1) is overexpressed in HER2+I. PI3K is overexpressed in BA, but not in HER2+I. PDK1, which phosphorylates and activates AKT, is over-expressed in HER2+I but not in BA. We also found that TNFα - an initiator of the canonical NF-κB activation pathway - is over-expressed in BA.
 In the HER2+I subtype, the overexpression of NIK, the absence of high expression of TRAF2/5, which recruits the IKK complex and also the low expression of IKKβ suggest that NF-κB is activated via the alternative pathway. In the BA subtype, the overexpression of TRAF3, a known inhibitor of the alternative pathway, suggests that the activation of NF-κB may occur via the canonical pathway.
 Boehm et al (Cell, 2007) shown that NF-κB can be inhibited by simultaneously targeting AKT and IKBKE. Their finding raises the interesting possibility of developing a targeted therapy for the BA and HER+ breast tumors.