Abstract 418: Cellular mechanisms underlying the evasion of detachment-induced cell death in inflammatory breast cancer cells

Abstract

Abstract Inflammatory Breast Cancer (IBC) is a rare and aggressive form of breast cancer that results from cancerous epithelial cells that invade and block the lymphatic vessels. Because the cancerous cells have already migrated from the epithelium into the lymphatic system, these cells are inherently metastatic and have the ability to survive in the absence of attachment to the extracellular matrix (ECM). Non-cancerous epithelial cells require ECM attachment for normal cell signaling and survival, however IBC cells are able to persist without ECM attachment in the lymphatic vessels. Here we demonstrate that both the SUM149 and the ErbB2-overexpressing SUM190 cell lines derived from primary IBC tumors have acquired mechanisms to aid in their survival in detached environments. Using an in vitro model of ECM detachment, we reveal that detached IBC cells exhibit a dramatic evasion of anoikis (detachment-induced apoptosis). In the SUM149 cells, this evasion of anoikis seems to be mediated by the MAPK pathway as inhibition of this pathway with UO126 abrogates the inhibition of detachment-induced caspase activation. However, the evasion of anoikis in SUM190 cells is unaffected by U0126 treatment and is instead mediated by the PI(3)K pathway. Furthermore, when compared to the SUM149 cells, the SUM190 cells are much more effective at inhibiting anoikis. Interestingly, SUM190 cells exhibit a complete inhibition of the ECM-detachment-induced increase in pro-caspase-3, a mechanism that may explain the more efficient anoikis inhibition in these cells. Additionally, both the SUM149 cells and the SUM190 cells are able to overcome detachment-induced metabolic stress. This is demonstrated through the ability of both the SUM149 and SUM190 cells to maintain ATP levels upon detachment. However, while western blotting clearly demonstrates detachment-induced PI(3)K activation in both cell lines, we have discovered that this upregulation is necessary for metabolic rescue only in the SUM149 cell line. Neither the MAPK nor PI(3)K pathway is involved in the maintenance of ATP following ECM detachment, suggesting that these cells may utilize an alternative signaling pathway to maintain ATP levels. These results show that IBC cells have the capacity to alter both apoptotic and metabolic pathways to survive in detached environments. Further elucidation of these mechanisms may reveal new chemotherapeutic targets that permit the specific elimination of detached IBC cells within the lymphatic system. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 418. doi:10.1158/1538-7445.AM2011-418