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Updated: Mar 8, 2026
Orthotopic Injection of Breast Cancer Cells into the Mammary Fat Pad of Mice to Study Tumor Growth.
Published on: February 8, 2015
Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice
Jeroen Overman1, Frank Fontaine1, Mehdi Moustaqil1,2
1Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
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.
Insights
This study identified a small molecule that disrupts SOX18 transcription factor interactions, offering a new therapeutic strategy. The compound effectively reduced tumor growth and metastasis in preclinical models, highlighting its potential for cancer treatment.
Area of Science:
- Molecular Biology
- Pharmacology
- Developmental Biology
Background:
- Targeting transcription factors for therapeutics is promising but challenging.
- Existing strategies like blocking DNA binding or protein interactions have limited success.
- Transcription factors function in complex networks, complicating single-target inhibition.
Purpose of the Study:
- To discover protein-protein interactions of the SOX18 transcription factor.
- To develop a small molecule that disrupts specific SOX18 interactions.
- To evaluate the therapeutic potential of this small molecule in disease models.
Main Methods:
- Genomic, proteomic, and biophysical techniques were employed.
- A small molecule was designed to disrupt SOX18 protein interactions.
- In vitro assays, zebrafish larvae, and mouse breast cancer models were used for evaluation.
Main Results:
- A novel small molecule disrupted a subset of SOX18-dependent interactions.
- The compound selectively suppressed SOX18 transcriptional activity in vitro.
- In vivo, it interfered with vascular development in zebrafish and reduced tumor vascularity and metastasis in mice, improving survival.
Conclusions:
- An interactome-based strategy can effectively modulate transcription factor activity.
- This approach offers a novel therapeutic avenue for diseases involving SOX18.
- The developed small molecule shows promise for cancer treatment by targeting tumor angiogenesis and metastasis.
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