Overexpression of the epidermal growth factor receptor family member Her-2/neu 
in breast cancer leads to autophosphorylation of the receptor and induction of 
multiple downstream signaling pathways, including the Akt kinase to nuclear 
factor-kappaB (NF-kappaB) cascade that is associated with poor prognosis. 
Previously, we showed that the green tea polyphenol epigallocatechin 3-gallate 
(EGCG) inhibits growth of NF639 Her-2/neu-driven breast cancer cells via 
reducing receptor autophosphorylation and downstream Akt and NF-kappaB 
activities. Interestingly, upon prolonged culture in the presence of EGCG, cells 
resistant to the polyphenol could be isolated. Here, we report that resistant 
cells have lost tyrosine phosphorylation on the Her-2/neu receptor. 
Surprisingly, they displayed elevated NF-kappaB activity, and inhibition of this 
activity sensitized cells to EGCG. Data from microarray studies of the original 
and resistant NF639 populations of cells were subjected to Gene Set Enrichment 
Analysis pathway assessment, which revealed that the mitogen activated protein 
kinase (MAPK) pathway was activated in the resistant cells. Treatment of the 
resistant cells with the MAPK inhibitor U0216 reduced growth in soft agar and 
invasive phenotype, whereas the combination of EGCG and U0216 resulted in cells 
with a cobblestone epithelial phenotype. Thus, activation of the MAPK pathway 
mediates resistance to EGCG.