PUBLICATION

Molecular and functional interactions between AKT and SOX2 in breast carcinoma

Authors
Schaefer, T., Wang, H., Mir, P., Konantz, M., Pereboom, T.C., Paczulla, A.M., Merz, B., Fehm, T., Perner, S., Rothfuss, O.C., Kanz, L., Schulze-Osthoff, K., Lengerke, C.
ID
ZDB-PUB-170214-89
Date
2015
Source
Oncotarget   6: 43540-56 (Journal)
Registered Authors
Konantz, Martina, Lengerke, Claudia, Pereboom, Tamara, Wang, Hui
Keywords
AKT, SOX2, breast carcinoma, cancer stem cells, clonogenicity
MeSH Terms
  • Animals
  • Breast Neoplasms/metabolism*
  • Breast Neoplasms/pathology
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic/physiology
  • Heterografts
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Neoplastic Stem Cells/metabolism*
  • Neoplastic Stem Cells/pathology
  • Proto-Oncogene Proteins c-akt/metabolism*
  • Real-Time Polymerase Chain Reaction
  • SOXB1 Transcription Factors/metabolism*
  • Transduction, Genetic
  • Zebrafish
PubMed
26498353 Full text @ Oncotarget
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping