P2-01-13: Impact of Erlotinib on MSC-Mediated TIC Expansion and EMT.

Abstract

Abstract Background: Recently, we have demonstrated that mesenchymal stem cells (MSC) and MSC secreted factors (MSC-CM) have a profound effect on tumor initiating cells (TIC) enriched mammosphere formation and latency of tumor xenografts formation from breast cancer cell lines. Furthermore these interactions increased the expression of epithelial mesenchymal transition (EMT)-associated proteins which are associated with tumor cell invasion and metastasis as well as the TIC phenotype. (Klopp, A. H. et al., 2010, PLoS One. 5, e12180). Our data suggest that the presence of MSC in the tumor microenvironment may increase metastases by conferring stem progenitor cell biology on more differentiated non-metastatic cells. In addition, preliminary data suggested MSC-CM upregulated EGFR signaling in breast cancer cells. Therefore, we hypothesized that inhibiting EGFR signaling with erlotinib (tyrosin kinase inhibitor) can suppress MSC-mediated TIC expansion and EMT. Methods & Results: In order to demonstrate that erlotinib inhibits MSC-CM promoted expansion of TIC, we cultured breast cancer cells lines (SUM149, SUM159, SUM190, MDA-IBC3 and MCF-7) in anchorage independent conditions with MSC-CM and treated them with increasing concentrations of erlotinib. The efficiency of mammosphere formation was examined after 5 days. We found that erlotinib inhibited MSC mediated increase in mammosphere formation in triple negative cell lines SUM149 and SUM159, and HER2−positive cell lines SUM190 and MDA-IBC3, but not in ER-positive, erlotinib resistant MCF-7 cells. Furthermore, we evaluated the impact of erlotinib on cell cultures grown with breast cancer patient-derived fluids, such as seroma and malignant pleural effusions. We observed that the effect of erlotinib on mammospheres formation was attenuated by both types of patient fluids. Discussion: Patients with triple negative breast cancer have the highest rates of metastases and no available targeted therapies for treatment. EGFR is expressed in a significant proportion of triple negative breast cancers, and recent clinical and preclinical studies suggest that EGFR may contribute to the metastasis or aggressiveness of triple negative breast cancer. Here we demonstrate that host and environmentally-derived factors are critical for determining resistance to erlotinib. In vivo studies regarding the ability of erlotininb to prevent MSC-enhanced TIC survival and metastases are underway. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-01-13.