Abstract 579: 3, 3′-diindolylmethane enhances the effectiveness of Herceptin by upregulation of miR-200 through down-regulation of FoxM1 in breast cancer cells

Abstract

Abstract Many patients with high levels of HER2/neu experience disease progression even when treated with Herceptin as a single agent. Current Herceptin-based combination therapies involving conventional chemotherapeutic drugs have been shown to increase survival rate in only a portion of patients with high levels of HER2/neu. Furthermore, these treatments are associated with several toxicities. Thus, there is a strong need for developing new tumor selective agents that can be co-administered with Herceptin successfully, and with minimal toxicity, to treat breast cancer patients whose tumors express high levels of HER2/neu. 3,3′-diindolylmethane (DIM), a cruciferous plant-derived and non-toxic chemopreventive agent, has been reported to selectively kill breast cancer cells without affecting normal cells and sensitizes breast cancer cells to chemotherapeutic agents. In this study, we evaluated the effects of Herceptin alone and in combination with DIM on cell viability, apoptosis and clonogenic assays in SKBR3 (HER2/neu overexpressing) and MDA-MB-468 (HER2/neu-negative) breast cancer cell lines. We found that DIM could sensitize breast cancer cells to Herceptin by significantly reducing cell viability, which was associated with the induction of apoptosis and significant inhibition of colony formation when compared with single agent treatment. These results were also consistent with the down-regulation of Akt and NF-κB. Mechanistic investigations revealed a significant upregulation of miR-200, which resulted in the reduction of FoxM1 expression in DIM plus Herceptin-treated breast cancer cells. These results provide experimental evidence, for the first time, that DIM plus Herceptin therapy could be translated to the clinic as a therapeutic modality to improve treatment outcome of patients whose tumors express high levels of HER2/neu. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 579. doi:1538-7445.AM2012-579