Document Detail


Bcl-xL mediates therapeutic resistance of a mesenchymal breast cancer cell subpopulation.
MedLine Citation:
PMID:  25473892     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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.
Authors:
Ulrike Keitel; Andreas Scheel; Jürgen Thomale; Rovena Halpape; Silke Kaulfuß; Christina Scheel; Matthias Dobbelstein
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-11-17
Journal Detail:
Title:  Oncotarget     Volume:  -     ISSN:  1949-2553     ISO Abbreviation:  Oncotarget     Publication Date:  2014 Nov 
Date Detail:
Created Date:  2014-12-4     Completed Date:  -     Revised Date:  2014-12-5    
Medline Journal Info:
Nlm Unique ID:  101532965     Medline TA:  Oncotarget     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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