PUBLICATION

Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice

Authors
Overman, J., Fontaine, F., Moustaqil, M., Mittal, D., Sierecki, E., Sacilotto, N., Zuegg, J., Robertson, A.A., Holmes, K., Salim, A.A., Mamidyala, S., Butler, M.S., Robinson, A.S., Lesieur, E., Johnston, W., Alexandrov, K., Black, B.L., Hogan, B.M., Val, S., Capon, R.J., Carroll, J.S., Bailey, T.L., Koopman, P., Jauch, R., Smyth, M.J., Cooper, M.A., Gambin, Y., Francois, M.
ID
ZDB-PUB-170201-13
Date
2017
Source
eLIFE   6: (Journal)
Registered Authors
Black, Brian, Hogan, Ben M., Sacilotto, Natalia
Keywords
biochemistry, developmental biology, gene expression, mouse, protein protein interactions, small molecules, stem cells, transcription factors, tumour angiogenesis, zebrafish
MeSH Terms
  • Proteomics
  • Zebrafish Proteins/antagonists & inhibitors
  • Treatment Outcome
  • Disease Models, Animal
  • SOXF Transcription Factors/antagonists & inhibitors*
  • Blood Vessels/embryology
  • Mice
  • Biophysical Phenomena
  • Antineoplastic Agents/metabolism*
  • Zebrafish/embryology
  • Transcription, Genetic/drug effects*
  • Genomics
  • Breast Neoplasms/prevention & control*
  • Animals
(all 14)
PubMed
28137359 Full text @ Elife
Abstract
Pharmacological targeting of transcription factors holds great promise for the development of new therapeutics, but strategies based on blockade of DNA binding, nuclear shuttling, or individual protein partner recruitment have yielded limited success to date. Transcription factors typically engage in complex interaction networks, likely masking the effects of specifically inhibiting single protein-protein interactions. Here, we used a combination of genomic, proteomic and biophysical methods to discover a suite of protein-protein interactions involving the SOX18 transcription factor, a known regulator of vascular development and disease. We describe a small-molecule that is able to disrupt a discrete subset of SOX18-dependent interactions. This compound selectively suppressed SOX18 transcriptional outputs in vitro and interfered with vascular development in zebrafish larvae. In a mouse pre-clinical model of breast cancer, treatment with this inhibitor significantly improved survival by reducing tumour vascular density and metastatic spread. Our studies validate an interactome-based molecular strategy to interfere with transcription factor activity, for the development of novel disease therapeutics.
Errata / Notes
Corrected by: ZDB-PUB-230810-50
Genes / Markers
Figures
Figure Gallery (3 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
lcr1TgTransgenic Insertion
    s843TgTransgenic Insertion
      s896TgTransgenic Insertion
        y1TgTransgenic Insertion
          1 - 4 of 4
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          Human Disease / Model
          No data available
          Sequence Targeting Reagents
          Target Reagent Reagent Type
          rbpjaMO4-rbpja,rbpjbMRPHLNO
          rbpjbMO4-rbpja,rbpjbMRPHLNO
          sox7MO1-sox7MRPHLNO
          sox7MO2-sox7MRPHLNO
          sox18MO1-sox18MRPHLNO
          sox18MO2-sox18MRPHLNO
          1 - 6 of 6
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          Fish
          Antibodies
          No data available
          Orthology
          No data available
          Engineered Foreign Genes
          Marker Marker Type Name
          EGFPEFGEGFP
          mCherryEFGmCherry
          1 - 2 of 2
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          Mapping
          No data available