Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration

• Published in: Cell death and differentiation Vol. 22; no. 8; pp. 1275 - 1286
• Main Authors: Buchheit, C L, Angarola, B L, Steiner, A, Weigel, K J, Schafer, Z T
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2015; Nature Publishing Group
• Subjects: 13; 13/2; 631/67/322; 96; 96/106; 96/109; Anoikis - genetics; Anoikis - physiology; Apoptosis; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Bcl-2-Like Protein 11; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Cell Line; Cell Survival - genetics; Cell Survival - physiology; Humans; Immunoblotting; Immunohistochemistry; Inflammatory Breast Neoplasms - genetics; Inflammatory Breast Neoplasms - metabolism; Inflammatory Breast Neoplasms - pathology; Life Sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Models, Biological; Original Paper; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Stem Cells
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2014.209

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). ErbB2 and EGFR knockdown in KPL-4 and SUM149 cells, respectively, causes decreased colony growth in soft agar and increased caspase activation following ECM detachment. ERK/MAPK signaling was found to operate downstream of ErbB2 and EGFR to protect cells from anoikis by facilitating the formation of a protein complex containing Bim-EL, LC8, and Beclin-1. This complex forms as a result of Bim-EL phosphorylation on serine 59, and thus Bim-EL cannot localize to the mitochondria and cause anoikis. These results reveal a novel mechanism that could be targeted with innovative therapeutics to induce anoikis in IBC cells.