Effect of therapeutic targeting of the oncogene EMP2 in triple-negative breast cancer on tumor load.

Abstract

1052 Background: Understanding tumor induced angiogenesis is a challenging problem with important consequences for the diagnosis and treatment of cancer. In this study we define a novel function for the tetraspan epithelial membrane protein-2 (EMP2) in the control of neoangiogenesis. 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 highly expressed on the majority of invasive tumors examined, and in particular 70% of triple negative breast tumors showed surface expression of this marker. In this study, we examine the control of EMP2 on the tumor microenvironment and further characterize its therapeutic efficacy in breast cancer. Methods: A number of cancer cell lines were utilized both in vitro and in vivo to determine if EMP2 expression levels altered the tumor microenvironment. Cells were tested for their expression of pro-angiogenic proteins HIF-1a and VEGF-A as well as for their ability to induce endothelial cell migration and capillary like tube formation. Cells with modulated EMP2 levels were also tested in vivo for tumor formation and examined for histological changes in the tumor microenvironment. In addition, we recently constructed a fully human EMP2 IgG1 and determined its therapeutic efficacy in a number of triple negative breast cancer cells. Results: In vitro, upregulation of EMP2 promoted VEGF expression through a HIF-1a dependent pathway and resulted in successful capillary-like tube formation. In contrast, reduction of EMP2 correlated with reduced HIF-1a and VEGF expression with the net consequence of poorly vascularized tumors in vivo. Treatment of breast cancer cells with EMP2 IgG1 reduced tumor load with a significant improvement in survival. Conclusions: Clinically, EMP2 has been shown to correlate with poor survival, and these results suggest that this occurs in part through its control on tumor vasculature. In addition, we provide additional evidence on the potent cytotoxic effects of EMP2 treatment in vivo.