Priority Research Papers:

Bcl-xL mediates therapeutic resistance of a mesenchymal breast cancer cell subpopulation

Ulrike Keitel _, Andreas Scheel, Jürgen Thomale, Rovena Halpape, Silke Kaulfuß, Christina Scheel and Matthias Dobbelstein

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Oncotarget. 2014; 5:11778-11791. https://doi.org/10.18632/oncotarget.2634

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Ulrike Keitel1, Andreas Scheel2, Jürgen Thomale3, Rovena Halpape4, Silke Kaulfuß4, Christina Scheel5,6, Matthias Dobbelstein1

1Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), Faculty of Medicine, University of Göttingen, Göttingen 37077, Germany

2Institute of Pathology Nordhessen, Kassel 34119, Germany

3Institute of Cell Biology (Cancer Research), Faculty of Medicine, University Duisburg-Essen, Essen 45122, Germany

4Institute of Human Genetics, University Medical Center Göttingen, Göttingen 37073, Germany

5Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA

6Institute for Stem Cell Research, Helmholz Center Munich, Neuherberg 85764, Germany

Correspondence to:

Matthias Dobbelstein, e-mail: [email protected]

Keywords: Bcl-xL, chemo-resistance, epithelial-mesenchymal transition, apoptosis, BH3-mimetic

Received: August 11, 2014     Accepted: October 23, 2014     Published: November 17, 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.

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