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Targeting Sox18 delays breast cancer in mice

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Targeting Sox18 delays breast cancer in mice

Jeroen Overman, Frank Fontaine, Emmanuelle Lesieur and Mat Francois from the UQ CCVB Transcriptional Regulation of Vessels Laboratory and their collaborators have discovered that breast cancer in a mouse model can be delayed by pharmacological targeting of the SOX18 transcription factor.

 

Their research findings, published in eLife, featured on the journal's online cover and were highlighted on the journal's facebook page

 

 

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.

 

 

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

Overman J, Fontaine F, Moustaqil M, Mittal D, Sierecki E, Sacilotto N, Zuegg J, Robertson AA, Holmes K, Salim AA, Mamidyala S, Butler MS, Robinson AS, Lesieur E, Johnston W, Alexandrov K, Black BL, Hogan BM, De Val S, Capon RJ, Carroll JS, Bailey TL, Koopman P, Jauch R, Smyth MJ, Cooper MA, Gambin Y, Francois M.

eLife 2017; 6:e21221.

 

 

Read the paper here