Jang et al. BMC Cancer 2010, 10:391 http://www.biomedcentral.com/1471-2407/10/391 R E S E A R C H A R T I C L E Open Access Degradation of HER2/neu by ANT2 shRNA suppresses migration and invasiveness of breast cancer cells Ji-Young Jang, Yoon-Kyung Jeon, Chul-Woo Kim* Abstract Background: In breast cancer, the HER2/neu oncoprotein, which belongs to the epidermal growth factor receptor family, may trigger activation of the phosphoinositide-3 kinase (PI3K)/Akt pathway, which controls cell proliferation, survival, migration, and invasion. In this study, we examined the question of whether or not adenine nucleotide translocase 2 (ANT2) short hairpin RNA (shRNA)-mediated down-regulation of HER2/neu and inhibitory effects on the PI3K/Akt signaling pathway suppressed migration and invasiveness of breast cancer cells. Methods: We utilized an ANT2 vector-based RNA interference approach to inhibition of ANT2 expression, and the HER2/neu-overexpressing human breast cancer cell line, SK-BR3, was used throughout the study. Results: In this study, ANT2 shRNA decreased HER2/neu protein levels by promoting degradation of HER2/neu protein through dissociation from heat shock protein 90 (HSP90). As a result, ANT2 shRNA induced inhibitory effects on the PI3K/Akt signaling pathway. Inhibition of PI3K/Akt signaling by ANT2 shRNA caused down-regulation of membrane-type 1 matrix metalloproteinase (MT1-MMP) and vascular endothelial growth factor (VEGF) expression, decreased matrix metalloproteinase 2 (MMP2) and MMP9 activity, and suppressed migration and invasion of breast cancer cells. Conclusions: These results indicate that knock-down of ANT2 by shRNA down-regulates HER2/neu through suppression of HSP90’s function and inhibits the PI3K/Akt signaling pathway, resulting ultimately in suppressed migration and invasion of breast cancer cells. Background Breast cancer is the most common cancer among women in the western world and the second leading cause of cancer related death in women [1]. Gene ampli- fication and/or overexpression of some oncogenes have been implicated in development and progression of breast cancers. HER2/neu (also known as ErbB2) is one of the best characterized oncogenes linked with poor prognosis of breast cancer [2]. Overexpression of HER2/ neu is found in about 30% of human breast cancers and correlates with more aggressive tumors and greater resistance to cancer chemotherapy [3]. The HER2/neu oncoprotein is a transmembrane receptor, belonging to the epidermal growth factor * Correspondence: cwkim@snu.ac.kr Department of Pathology, Tumor Immunity Medical Research Center, Cancer Research Institute, Seoul National University College of Medicine, 28 Yongon-dong, Jongno-gu, Seoul 110-799, South Korea receptor family, with tyrosine kinase activity, resulting in intracellular signaling and activation of genes involved in cell growth, which is associated with shor- tened survival, enhanced aggressiveness, and other poor prognostic factors in breast cancer [4]. Activation of HER2/neu may trigger activation of downstream signal- ing pathways, such as the phosphoinositide-3 kinase (PI3K)/Akt pathway, which, controls cell proliferation, survival, migration, and invasion [5]. Studies performed in animal models have shown that down regulation of HER2/neu by repression of the HER2/neu promoter or by use of anti-HER2/neu antibodies can suppress tumor growth and dissemination. One therapeutic approach that has already reached clinical application is the use of an unarmed monoclonal antibody known as Trastu- zumab (Herceptin™). Studies have attributed the thera- peutic potential of anti-HER2/neu antibodies to their ability to enhance intracellular degradation of the cell © 2010 Jang et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.