NF-κB activation in inflammatory breast cancer is associated with oestrogen receptor downregulation, secondary to EGFR and/or ErbB2 overexpression and MAPK hyperactivation

Activation of NF-kappa B in inflammatory breast cancer (IBC) is associated with loss of estrogen receptor ( ER) expression, indicating a potential crosstalk between NF-kappa B and ER. In this study, we examined the activation of NF-kappa B in IBC and non-IBC with respect to ER and EGFR and/or ErbB2 expression and MAPK hyperactivation. A qRT-PCR based ER signature was evaluated in tumours with and without transcriptionally active NF-kappa B, as well as correlated with the expression of eight NF-kappa B target genes. Using a combined ER/ NF-kappa B signature, hierarchical clustering was executed. Hyperactivation of MAPK was investigated using a recently described MAPK signature (Creighton et al, 2006), and was linked to tumour phenotype, ER and EGFR and/or ErbB2 overexpression. The expression of most ER-modulated genes was significantly elevated in breast tumours without transcriptionally active NF-kB. In addition, the expression of most ER-modulated genes was significantly anticorrelated with the expression of most NF-kappa B target genes, indicating an inverse correlation between ER and NF-kappa B activation. Clustering using the combined ER and NF-kappa B signature revealed one cluster mainly characterised by low NF-kappa B target gene expression and a second one with elevated NF-kappa B target gene expression. The first cluster was mainly characterised by non-IBC specimens and IHC ER + breast tumours ( 13 out of 18 and 15 out of 18 respectively), whereas the second cluster was mainly characterised by IBC specimens and IHC ER-breast tumours ( 12 out of 19 and 15 out of 19 respectively) ( Pearson chi(2), P < 0.0001 and P < 0.0001 respectively). Hyperactivation of MAPK was associated with both ER status and tumour phenotype by unsupervised hierarchical clustering using the MAPK signature and was significantly reflected by overexpression of EGFR and/or ErbB2. NF-kappa B activation is linked to loss of ER expression and activation in IBC and in breast cancer in general. The inverse correlation between NF-kappa B activation and ER activation is due to EGFR and/or ErbB2 overexpression, resulting in NF-kappa B activation and ER downregulation.