HRAP, a pentapeptide designed to bind with the pertuzumab interacting site in an extracellular domain of the HER2 molecule, enhanced the cytotoxicity of paclitaxel in HER2-overexpressing human breast cancer cell lines, BT474 and SKBR-3, but not in MDA-231 cells, which express lower levels of HER2. HRAP enhanced mitochondria-dependent apoptosis induced by paclitaxel in SKBR-3 and BT-474, but not in MDA-231. HRAP enhanced the inhibition of phosphorylation of serine 473 in Akt and Ser380/Thy382/The383 in PTEN. These results suggest that HRAP enhances paclitaxel-induced apoptosis in a manner dependent on the PTEN/AKt signal transduction pathway. (C) 2010, The Society for Biotechnology, Japan. All rights reserved.