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

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...

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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
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1350-9047 1476-5403
DOI:	10.1038/cdd.2014.209