title: Bcl-xL mediates therapeutic resistance of a mesenchymal breast cancer cell subpopulation.
abstract: 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.affiliation: Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), Faculty of Medicine, University of Göttingen, Göttingen 37077, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Keitel
authors.affiliation: Institute of Pathology Nordhessen, Kassel 34119, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Scheel
authors.affiliation: Institute of Cell Biology (Cancer Research), Faculty of Medicine, University Duisburg-Essen, Essen 45122, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Thomale
authors.affiliation: Institute of Human Genetics, University Medical Center Göttingen, Göttingen 37073, Germany.
authors.forename: Rovena
authors.initials: R
authors.lastname: Halpape
authors.affiliation: Institute of Human Genetics, University Medical Center Göttingen, Göttingen 37073, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Kaulfuß
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Institute for Stem Cell Research, Helmholz Center Munich, Neuherberg 85764, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Scheel
authors.affiliation: Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), Faculty of Medicine, University of Göttingen, Göttingen 37077, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Dobbelstein
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D005455:Fluorescent Antibody Technique; D064593:Heterografts; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D059467:Transcriptome; D051020:bcl-X Protein / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C494811:BCL2L1 protein, human; D051020:bcl-X Protein