Development of her2-antagonistic peptides as novel anti-breast cancer drugs by in silico methods

Abstract

14014 Background: The overexpression of HER2 in breast cancer correlates well with increased tumor growth and metastatic potential, and thereby poor long-term survival for the patients. Therefore, therapeutic approaches are being developed to block the effects of HER2 overexpression in breast cancer by a monoclonal antibody, called trastuzumab. Based on these results, we are trying to design and produce antibody-mimetic peptide molecules using our in silico design method. Here, we report the creation of a novel peptide (HRAP: HER2 Reactive Peptide) that is able to antagonize HER2 signaling pathway. Methods: An antagonistic peptide called HRAP that binds to the human HER2 molecule was designed by our computational method. Peptides were synthesized by a peptide synthesizer. Human breast cancer cell lines, i.e. KPL-4, MDA231, BT-474, and SKBR-3, which express HER2 at various levels were used in this study. Cell proliferation was assayed using BrdU kit. Cell viability was measured by an MTT assay. Immunodetection of various protein expressions were performed by western blotting. Results: In silico docking study demonstrated the specific interaction of HRAP with the dimerization domain in the HER2 molecule. Interestingly, HRAP inhibited proliferation of HER2-overexpressed human breast cancer cell lines. However, it had little cellular cytotoxicity (apoptosis inducibility). The cell proliferation inhibition was associated with the suppression of phosphorylation of PTEN and Akt. Conclusions: HRAP is the first HER2-binding small peptide antagonist rationally designed by a computer-aided method and is useful for the development of peptide mimetics to generate novel anti-breast cancer drugs for HER2 expressing tumors. No significant financial relationships to disclose.