Abstract 240: Therapeutic targeting of EMP2 reduces breast cancer stem cells.

Abstract

Abstract There is increasing evidence that tumor-initiating cancer stem cells (CSCs) contribute to tumor metastasis and therapeutic resistance. In breast cancer, metastatic CSCs are defined as CD44+/CD24- and ALDH+, and in this study, we define another marker epithelial membrane protein-2 (EMP2) as a novel target for this population of cells. EMP2 is an oncogene whose expression has been shown to correlate with tumor progression and survival in a number of human cancers including triple negative breast, ovarian, and endometrial tumors. In breast cancer, EMP2 is expressed on the majority of invasive tumors examined, and in particular 70% of triple negative breast tumors showed surface expression of this marker. Clinical data also revealed higher levels of EMP2 in metastatic lesions compared to primary tumors. In this study, we show new evidence that EMP2 is highly expressed in CSCs. New data suggests that EMP2 upregulates the expression of HIF-1α, CD44, and ALDH and directly contributes to the metastatic potential of the tumor cell. High levels of EMP2 promote mammosphere formation and increased tumor forming potential. In tumors created from these cells, high levels of ALDH+ expression were also observed. In contrast, reduction in EMP2 decreased CD44 expression and ALDH activity both in vitro and in vivo, with the net consequence of poorly vascularized and slow growing tumors. We have recently developed a novel IgG1 monoclonal antibody to EMP2 and have started testing its therapeutic efficacy. In vitro treatment with EMP2 IgG1 reduced HIF-1α, CD44, and ALDH levels, ultimately leading to caspase mediated apoptosis. Treatment of breast cancer cells with EMP2 IgG1 reduced tumor load in both subcutaneous and metastatic models of breast cancer with a significant improvement in survival. Histological examination of the tumors revealed significant necrosis and elimination of ALDH+ CSCs. These results suggest that targeting EMP2 may reduce CSCs and represent an attractive target for further therapeutic development. Citation Format: Madhuri Wadehra, Meagan Kiyohara, Negin Ashki. Therapeutic targeting of EMP2 reduces breast cancer stem cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 240. doi:10.1158/1538-7445.AM2013-240