Oncotarget

Research Papers:

Molecular and functional interactions between AKT and SOX2 in breast carcinoma

Thorsten Schaefer, Hui Wang, Perihan Mir, Martina Konantz, Tamara C. Pereboom, Anna M. Paczulla, Britta Merz, Tanja Fehm, Sven Perner, Oliver C. Rothfuss, Lothar Kanz, Klaus Schulze-Osthoff and Claudia Lengerke _

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Oncotarget. 2015; 6:43540-43556. https://doi.org/10.18632/oncotarget.6183

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Abstract

Thorsten Schaefer1,*, Hui Wang1,2,*, Perihan Mir2, Martina Konantz1, Tamara C. Pereboom1, Anna M. Paczulla1, Britta Merz3, Tanja Fehm4, Sven Perner5, Oliver C. Rothfuss3, Lothar Kanz2, Klaus Schulze-Osthoff3,6, Claudia Lengerke1,2,7

1Department of Biomedicine, University Hospital Basel, Basel, Switzerland

2Department of Internal Medicine II, University Hospital Tuebingen, Tuebingen, Germany

3Interfaculty Institute of Biochemistry, University of Tuebingen, Tuebingen, Germany

4Women's Hospital, University Hospital Duesseldorf, Duesseldorf, Germany

5Institute of Pathology, University of Luebeck, Luebeck, Germany

6German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany

7Clinic for Hematology, University Hospital Basel, Basel, Switzerland

*These authors have contributed equally to this work

Correspondence to:

Claudia Lengerke, e-mail: claudia.lengerke@unibas.ch

Keywords: SOX2, AKT, breast carcinoma, cancer stem cells, clonogenicity

Received: August 16, 2015     Accepted: October 10, 2015     Published: October 20, 2015

ABSTRACT

The transcription factor SOX2 is a key regulator of pluripotency in embryonic stem cells and plays important roles in early organogenesis. Recently, SOX2 expression was documented in various cancers and suggested as a cancer stem cell (CSC) marker. Here we identify the Ser/Thr-kinase AKT as an upstream regulator of SOX2 protein turnover in breast carcinoma (BC). SOX2 and pAKT are co-expressed and co-regulated in breast CSCs and depletion of either reduces clonogenicity. Ectopic SOX2 expression restores clonogenicity and in vivo tumorigenicity of AKT-inhibited cells, suggesting that SOX2 acts as a functional downstream AKT target. Mechanistically, we show that AKT physically interacts with the SOX2 protein to modulate its subcellular distribution. AKT kinase inhibition results in enhanced cytoplasmic retention of SOX2, presumably via impaired nuclear import, and in successive cytoplasmic proteasomal degradation of the protein. In line, blockade of either nuclear transport or proteasomal degradation rescues SOX2 expression in AKT-inhibited BC cells. Finally, AKT inhibitors efficiently suppress the growth of SOX2-expressing putative cancer stem cells, whereas conventional chemotherapeutics select for this population. Together, our results suggest the AKT/SOX2 molecular axis as a regulator of BC clonogenicity and AKT inhibitors as promising drugs for the treatment of SOX2-positive BC.


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