Effect of therapeutic targeting of EMP2 on breast and endometrial cancer stem cells.

Abstract

3080 Background: There is increasing evidence that tumor-initiating cancer stem cells (CSCs) contribute to tumor metastasis and therapeutic resistance. In breast and endometrial cancers, 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. Methods: A number of cancer cell lines were utilized both in vitro and in vivo to determine if EMP2 expression levels alter the number and expression of CSC markers. To translate this work, EMP2 and ALDH expression were correlated in primary human endometrial and breast cancers. To determine the therapeutic efficacy of our fully-human EMP2 IgG1 antibody, xenografts from breast or uterine cancer were treated, removed, and then reinjected into secondary mice. Results: In this study, we show new evidence that EMP2 is highly expressed in CSCs. High levels of EMP2 increase the tumor forming potential of both endometrial and breast cancer lines. 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 monoclonal antibody to EMP2 and have started testing its therapeutic efficacy. In vitro treatment with EMP2 IgG1 reduced HIF-1a, 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 and endometrial cancer resulting in a significant improvement in survival. Reinjection of these cells post treatment into secondary mice failed to efficiently form, and histological examination of the tumors revealed significant necrosis and elimination of ALDH+ CSCs. Conclusions: These results suggest that targeting EMP2 may reduce CSCs and represent an attractive target for further therapeutic development.