Abstract 1347: The role of cell-cell contacts in the survival of extracellular matrix detached mammary epithelial cells

Abstract

Abstract Normal epithelial cells require attachment to the extracellular matrix (ECM) in order to survive. When detached from the ECM, normal cells will undergo apoptosis through a process known as anoikis. The ErbB2 receptor tyrosine kinase is well known to antagonize anoikis although the precise molecular mechanisms are not entirely known. Interestingly, we have discovered that the overexpression of ErbB2 in non-malignant mammary epithelial cells (MCF-10A) results in substantial aggregation of cells that coincides with protection from anoikis. Therefore, we were interested in understanding if these aggregates could be involved in the evasion of anoikis induction. We found that the disruption of cell-cell contacts in ErbB2-overexpressing MCF-10A cells (using methylcellulose or by antagonizing the formation of adherens junctions) induces caspase activation. Furthermore, in cells that form large aggregates, ErbB2 can physically interact with E-cadherin and EGFR in a fashion that prevents the internalization of EGFR and ultimately its lysosome mediated degradation. The disruption of aggregation causes the ErbB2/EGFR/E-Cadherin complex to fall apart and subsequently results in EGFR degradation in the lysosome. This degradation of EGFR diminishes signaling through the MAPK pathway which prevents the induction of anoikis. In summary, these data suggest that oncogenic signaling through ErbB2 promotes the formation of cellular aggregates that function to prevent EGFR from degradation and subsequently to block the induction of anoikis. Citation Format: Raju Rayavarapu, Nicholas Pagani, Brendan Heiden, Zachary T. Schafer. The role of cell-cell contacts in the survival of extracellular matrix detached mammary epithelial cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1347. doi:10.1158/1538-7445.AM2014-1347