Abstract A197: Development of an immunocompetent, triple negative, breast cancer model for stem cell based delivery of therapeutics

Abstract

Abstract Breast cancer represents a broad-spectrum cancer with diverse morphological and immunohistochemical features and varied clinical outcomes. Affected breast cancer patients fall into one of three classifications: 1) hormone (estrogen receptor (ER), progesterone receptor (PR))-positive tumors, 2) tumors with demonstrated ERBB2 (HER2+) amplification and, 3) tumors that are ER−, PR− and ERBB2lo. For hormone receptor-positive (ER) tumors, a variety of ER-targeted therapy regimens with and without chemotherapy are available. Patients whose tumors are classified as ER−, PR− and ERBB2lo (triple negative breast cancer; TNBC) are largely limited to chemotherapy as the only therapeutic modality. We have developed an autologous, immunocompetent triple negative breast cancer (TNBC) model whose features may overcome deficiencies of xenograft models for development of TNBC therapeutics. The model consists of: FVB/N immunocompetent mice; bone derived mesenchymal stem cells (MSCs) from FVB/N mice; and a triple negative cell line (UMD-227), which is derived from a mammary tumor that developed in an NRL-TGFα FVB/N mouse. Our hypothesis is that expression of antitumor factors (interferon beta (IFNβ), TNF-related apoptosis-inducing ligand (TRAIL), and/or the epidermal growth factor receptor (EGFR) inhibitor decorin (DCN)) from MSCs, either singly or in combination, will efficiently kill triple negative breast cancers. To test this hypothesis in vitro, we have applied each therapeutic individually, as conditioned medium produced from MSCs, on our novel, triple negative, mouse mammary cancer line, UMD-227, and measured cell proliferation by a sulforhodamine B assay. In addition, we have tested for an additive effect with IFNβ and TRAIL using MSC/IFNβ conditioned media and commercial TRAIL. The addition of MSC/IFN conditioned medium to UMD-227 cells significantly inhibits their growth in a proliferation assay similar to that shown with the TNBC line MDA-MB-231. The addition of commercial TRAIL 24 hours after placing UMD-227 cells in MSC/IFNβ conditioned medium, produces a significant decrease in cell proliferation as compared to MSC/IFN conditioned medium alone or TRAIL alone. This is consistent with the knowledge that IFNβ upregulates TRAIL receptors, making the cell more susceptible to the addition of TRAIL at the 24 hour timepoint. These results suggest that MSCs engineered to express combinations of anticancer molecules may be a more efficacious therapeutic modality for TNBC. The next step in the development of our autologous immunocompetent triple breast cancer model is the insertion of multiple factors into the MSCs. We will then test the efficacy of the combinatorial therapy delivered from MSCs on the proliferation and motility of UMD-227s in vitro. Our final goal is to move the entire system into the autologous mouse model (NRL-TGFα) and test the efficacy of the combinatorial therapy in vivo. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A197.