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5-Aza-2ʹ-deoxycytidine (5-azaCdR) inhibits growth of breast cancer cells but increases their metastatic potential. Combining methylated DNA binding protein 2 depletion and 5-azaCdR has a synergistic antitumor effect enhancing tumor growth, while inhibiting invasiveness, pointing to a potential new epigenetic therapeutic for breast cancer.5-Aza-2ʹ-deoxycytidine (5-azaCdR) not only inhibits growth of non-invasive breast cancer cells but also increases their invasiveness through induction of pro-metastatic genes. Methylated DNA binding protein 2 (MBD2) is involved in silencing methylated tumor suppressor genes as well as activation of pro-metastatic genes. In this study, we show that a combination of MBD2 depletion and DNA methyltransferases (DNMT) inhibition in breast cancer cells results in a combined effect in vitro and in vivo, enhancing tumor growth arrest on one hand, while inhibiting invasiveness triggered by 5-azaCdR on the other hand. The combined treatment of MBD2 depletion and 5-azaCdR suppresses and augments distinct gene networks that are induced by DNMT inhibition alone. These data point to a potential new approach in targeting the DNA methylation machinery by combination of MBD2 and DNMT inhibitors. [ABSTRACT FROM AUTHOR]