S14 as a Therapeutic Target in Breast Cancer
Annual rept. 15 Jul 2003-14 Jul 2004
DARTMOUTH COLL HANOVER NH
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This project is aimed at determining the importance of S14, a nuclear protein that signals for increased lipid synthesis in normal cells, to breast cancer biology. Our aims are first to develop a model of anti-S14 breast cancer therapy in mice. Intratumoral adenoviral delivery of an S14-antisense gene into human breast cancer cell xenografts caused a significant inhibition of tumor growth. Efforts are now directed at verifying the specificity of this effect using hairpin inhibitory RNA. To this end, we have tested two siRNAs in breast cancer cells in tissue culture, and achieved a major knockdown of 514 mRNA. Second, to define the structure of the S14 multimer by X-ray crystallography. S14 has proven very difficult to crystallize because of folding. We have defined the structure of peptides representing multimerization domains, indicating tetramer formation and the importance of specific residues. Third, to define the utility of S14 as a clinical marker. We developed excellent monoclonal antibodies for human S14, and have nearly completed immunohistochemical study of 100 cases for S14, cyclin D1, and fatty acid synthase to correlate with clinical markers. The most exciting result is that S14 is grossly overexpressed in the earliest stage of breast cancer DCIS.
- Anatomy and Physiology
- Medicine and Medical Research