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LEF1 supports metastatic brain colonization by regulating glutathione metabolism and increasing ROS resistance in breast cancer

 
: Blazquez, Raquel; Rietkötter, Eva; Wenske, Britta; Wlochowitz, Darius; Sparrer, Daniela; Vollmer, Elena; Müller, Gunnar; Seegerer, Julia; Sun, Xueni; Dettmer, Katja; Barrantes-Freer, Alonso; Stange, Lena; Utpatel, Kirsten; Bleckmann, Annalen; Treiber, Hannes; Bohnenberger, Hanibal; Lenz, Christof; Schulz, Matthias; Reimelt, Christian; Hackl, Christina; Grade, Marian; Büyüktas, Deram; Siam, Laila; Balkenhol, Marko; Stadelmann, Christine; Kube, Dieter; Krahn, Michael P.; Proescholdt, Martin A.; Riemenschneider, Markus J.; Evert, Matthias; Oefner, Peter J.; Klein, Christoph A.; Hanisch, Uwe K.; Binder, Claudia; Pukrop, Tobias

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Fulltext urn:nbn:de:0011-n-5746684 (3.7 MByte PDF)
MD5 Fingerprint: 2f492b3064137d724424da7ce6160d40
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Created on: 28.1.2020


International journal of cancer 146 (2020), No.11, pp.3170-3183
ISSN: 0020-7136
ISSN: 1097-0215
English
Journal Article, Electronic Publication
Fraunhofer ITEM ()
Brain metastasis; Glutathione; LEF1; Metastatic colonization; ROS

Abstract
More than half of all brain metastases show infiltrating rather than displacing growth at the macro-metastasis/brain parenchyma interface (MMPI), a finding associated with shorter survival. The Lymphoid Enhancer-binding Factor-1 (LEF1) is an epithelial-mesenchymal transition (EMT) transcription factor that is commonly overexpressed in brain-colonizing cancer cells. Here, we overexpressed LEF1 in an in vivo breast cancer brain colonization model. It shortened survival, albeit without engaging EMT at the MMPI. By differential proteome analysis, we identified a novel function of LEF1 as a regulator of the glutathione (GSH) system, the principal cellular redox buffer. LEF1 overexpression also conferred resistance against therapeutic GSH depletion during brain colonization and improved management of intracellular ROS. We conclude that besides EMT, LEF1 facilitates metastasis by improving the anti-oxidative capacity of epithelial breast cancer cells, in particular during colonization of the brain parenchyma. This article is protected by copyright. All rights reserved.

: http://publica.fraunhofer.de/documents/N-574668.html