Molecular and functional interactions between AKT and SOX2 in breast carcinoma.
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.
Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
Thorsten
T
Schaefer
Department of Biomedicine, University Hospital Basel, Basel, Switzerland.|Department of Internal Medicine II, University Hospital Tuebingen, Tuebingen, Germany.
Hui
H
Wang
Department of Internal Medicine II, University Hospital Tuebingen, Tuebingen, Germany.
Perihan
P
Mir
Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
Martina
M
Konantz
Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
Tamara C
TC
Pereboom
Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
Anna M
AM
Paczulla
Interfaculty Institute of Biochemistry, University of Tuebingen, Tuebingen, Germany.
Britta
B
Merz
Women's Hospital, University Hospital Duesseldorf, Duesseldorf, Germany.
Tanja
T
Fehm
Institute of Pathology, University of Luebeck, Luebeck, Germany.
Sven
S
Perner
Interfaculty Institute of Biochemistry, University of Tuebingen, Tuebingen, Germany.
Oliver C
OC
Rothfuss
Department of Internal Medicine II, University Hospital Tuebingen, Tuebingen, Germany.
Lothar
L
Kanz
Interfaculty Institute of Biochemistry, University of Tuebingen, Tuebingen, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Klaus
K
Schulze-Osthoff
Department of Biomedicine, University Hospital Basel, Basel, Switzerland.|Department of Internal Medicine II, University Hospital Tuebingen, Tuebingen, Germany.|Clinic for Hematology, University Hospital Basel, Basel, Switzerland.
Claudia
C
Lengerke
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D064593:Heterografts; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D014161:Transduction, Genetic; D015027:Zebrafish
C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D051057:Proto-Oncogene Proteins c-akt
AKT; SOX2; breast carcinoma; cancer stem cells; clonogenicity