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Bcl-xL mediates therapeutic resistance of a mesenchymal breast cancer cell subpopulation.
Oncotarget 5, 11778-11791 (2014)
The transition from an epithelial to a mesenchymal phenotype (EMT) confers increased invasiveness and clonogenic potential to tumor cells. We used a breast epithelium-derived cell culture model to evaluate the impact of EMT on the cellular sensitivity towards chemotherapeutics and apoptotic stimuli. Cells that had passed through an EMT acquired resistance towards chemotherapeutics and death ligands. Mechanistically, we found that the levels of the apoptosis inhibitor Bcl-xL were strongly enhanced in mesenchymal versus epithelial cells, whereas the pro-apoptotic proteins Bim and Puma were diminished. Clinical samples from breast cancer showed enhanced Bcl-xL staining in cells that had dispersed into the desmoplastic stroma, as compared to cells that were part of large tumor cell aggregates, suggesting increased Bcl-xL expression when cells invade the stroma. Bcl-xL was necessary for apoptotic resistance in mesenchymal cells, and its expression was sufficient to confer such resistance to epithelial cells. To antagonize Bcl-xL, BH3-mimetics were used. They successfully interfered with the proliferation and survival of mesenchymal cells, and also inhibited the growth of xenograft tumors raised from the mesenchymal subpopulation. We conclude that enhanced Bcl-xL levels confer resistance to cells upon EMT, and that Bcl-xL represents a promising target for therapy directed against invasive cancer cells.
Impact Factor
Scopus SNIP
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Times Cited
Times Cited
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Cited By
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6.627
1.383
21
23
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Bcl-xl ; Chemo-resistance ; Epithelial-mesenchymal Transition ; Apoptosis ; Bh3-mimetic; Stem-cells; Carcinoma Cells; Transition; Proteins; Progression; Paclitaxel; Plasticity; Phenotype; Apoptosis; Autophagy
Language
english
Publication Year
2014
HGF-reported in Year
2014
ISSN (print) / ISBN
1949-2553
e-ISSN
1949-2553
Journal
OncoTarget
Quellenangaben
Volume: 5,
Issue: 23,
Pages: 11778-11791
Publisher
Impact Journals LLC
Reviewing status
Peer reviewed
Institute(s)
Institute of Stem Cell Research (ISF)
POF-Topic(s)
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s)
Stem Cell and Neuroscience
PSP Element(s)
G-552300-001
PubMed ID
25473892
WOS ID
WOS:000348037700002
Erfassungsdatum
2014-12-06