The ErbB2 receptor tyrosine kinase is overexpressed in approximately 30% of 
breast tumor cases and its overexpression correlates with an unfavorable 
prognosis. A major contributor for this course of the disease is the 
insensitivity of these tumors toward chemotherapy. Monoclonal antibodies, 
inhibiting the ligand-induced activation of the receptor and tyrosine kinase 
inhibitors acting on the intrinsic enzymatic activity of the intracellular 
domain, have been developed as targeted drugs. Both have been shown to be 
beneficial for breast cancer patients. We targeted a third aspect of receptor 
function: its association with intracellular signaling components. For this 
purpose, we selected peptide aptamers, which specifically interact with defined 
domains of the intracellular part of the receptor. The peptide aptamers were 
selected from a random peptide library using a yeast two-hybrid system with the 
intracellular tyrosine kinase domain of ErbB2 as a bait construct. The peptide 
aptamer AII-7 interacts with high specificity with the ErbB2 receptor in vitro 
and in vivo. The aptamers colocalized with the intracellular domain of ErbB2 
within cells. We investigated the functional consequences of the aptamer 
interaction with the ErbB2 receptor within tumor cells. The aptamer sequences 
were either expressed intracellularly or introduced into the cells as 
recombinant aptamer proteins. The phosphorylation of p42/44 mitogen-activated 
protein kinase was nearly unaffected and the activation of signal transducers 
and activators of transcription-3 was only modestly reduced. In contrast, they 
strongly inhibited the induction of AKT kinase in MCF7 breast cancer cells 
treated with heregulin, whereas AKT activation downstream of insulin-like growth 
factor I or epidermal growth factor receptor was not or only slightly affected. 
High AKT activity is responsible for the enhanced resistance of 
ErbB2-overexpressing cancer cells toward chemotherapeutic agents. Peptide 
aptamer interference with AKT activation resulted in the restoration of regular 
sensitivity of breast cancer cells toward Taxol.