S14 as a Therapeutic Target in Breast Cancer
DARTMOUTH COLL HANOVER NH
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This project aimed to determine the importance of S14, a nuclear protein that signals for lipid synthesis in breast cancer. Our aims were first to develop a model of anti-S14 breast cancer therapy. Intratumoral adenoviral delivery of an S14-antisense gene into human breast cancer cell xenografts significantly inhibited tumor growth and we verified the specificity of this effect using siRNA. We identified two siRNAs that knockdown S14 protein in breast cancer cells and found them to be cytotoxic. Second to define the structure of the S14 multimer. S14 proved very difficult to crystallize. We therefore used NMR and computer modeling to discern the structure of the S14 tetramerization domain and identified key residues for multimer assembly by mutagenesis. Third to define the utility of S14 as a clinical marker. We produced S14 antibodies for immunohistochemistry. This revealed strong associations of S14 staining with tumor size and grade and a striking power to predict tumor recurrence. Thus S14 is a driver and a marker of virulent breast cancer that identifies cases that are likely to recur.
- Anatomy and Physiology
- Medicine and Medical Research