Abstract 2080: The role of ErbB2 in regulating survival in matrix-detached inflammatory breast cancer cells

Abstract

Abstract Inflammatory breast cancer (IBC) is a rare and highly invasive type of breast cancer, and patients diagnosed with IBC often face a very poor prognosis. IBC is characterized by the lack of primary tumor formation and the rapid accumulation of cancerous epithelial cells in the dermal lymphatic vessels. Given that normal epithelial cells require attachment to the extracellular matrix (ECM) for survival, a comprehensive examination of the molecular mechanisms underlying IBC cell survival in the lymphatic vessels is of paramount importance to our understanding of IBC pathogenesis. Here we demonstrate that in contrast to normal mammary epithelial cells, IBC cells evade ECM-detachment-induced apoptosis (anoikis) and maintain ATP levels following ECM detachment. Exogenous ErbB2 overexpression leads to increased ATP production and soft agar growth in IBC cells that normally lack ErbB2 amplification. Additionally, ErbB2 knockdown in KPL-4 cells, an IBC cell line characterized by high levels of ErbB2, resulted in diminished ATP levels, decreased colony growth, and increased caspase activation following ECM detachment. Further studies reveal that the protection from anoikis in IBC cells is dependent on activation of the ERK-MAPK pathway, but does not depend on modulation of the levels of the pro-apoptotic factor Bim. These results demonstrate that ErbB2 is necessary and sufficient for IBC cell survival in the absence of ECM attachment. Understanding the molecular mechanism utilized by IBC cells to survive in matrix-detached conditions could lead to more specific and effective therapeutics to prevent IBC metastasis from occurring and to treat patients in which metastasis has already occurred. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2080. doi:1538-7445.AM2012-2080