Description of Research Program
Colon and Breast Cancer: Protein Structure and Function, DNA Damage/Repair, Genomics and Oncogenic Pathways The research in the laboratory is focused on improving the therapeutic outcome of colon cancer and in identifying the molecular signatures of breast tumors that are associated with poor survival. One project is focused on identifying key residues that play a role in the structure and catalytic mechanism of a protein target of chemotherapy of colon cancer that has oncogenic activity. We have shown that the protein undergoes conformational switching between two structural forms. One goal of our research is to design novel inhibitors of the protein that are targeted at one of the structures as an approach to overcoming the resistance associated with current chemotherapy. A second goal is to elucidate the functional relevance of conformational switching in post-translational modification and protein turnover, in the binding of currently used chemotherapeutic drugs, and in the oncogenic activity of the protein. A second project is aimed at improving the antitumor effects of chemotherapy which inhibits tumor growth by causing DNA damage. We are analyzing the stress response pathways that are activated by DNA damage. Our focus is on the role between cell signaling pathways activated by DNA damage and alteration in the activity of membrane proteins that protect tumor and normal cells from genotoxic stress. The goal is to utilize this information to develop approaches that selectively inhibit tumor cells with minimal toxicity to normal cells. A third project is to identify the biological basis for the increased mortality rates of African-American (AA) women with breast cancer. We are comparing the patterns of gene expression in tumors from AA and European-American women to identify molecular signatures of the disease. We are also examining the relationships between nutritional status, DNA damage in peripheral blood lymphocytes, and the pathology of breast tumors in these populations. Our studies are aimed at identifying biomarkers that are predictive of aggressive disease, with the goal of developing nutritional or chemopreventive approaches that prevent breast cancer or reduce the likelihood of the disease.
Selected Publications
Phan, J., Steadman, D.J., Koli, S., Ding, W.C., Minor, W., Dunlap, R.B., Berger, S.H., and Lebioda, L. Structure of Human Thymidylate Synthase Suggests Approaches for Noncompetitive Inhibition. J. Biol. Chem. 276:14170-14177 (2001).
SEQ CHAPTER \h
1Berger, S.H., Berger, F.G., and Lebioda, L. Ligand Binding, Conformational Switching, and Stability of Human Thymidylate Synthase. Biochim. Biophys. Acta 1696:15-22 (2004).
Li, L., Connor, E.E., Berger, S.H., and Wyatt, M.D., Determination of Apoptosis, Uracil Incorporation, DNA Strand Breaks, and Sister Chromatid Exchanges under Conditions of Thymidylate Deprivation in a Model of BER Deficiency. Biochem. Pharmacol. 70:1458-1468 (2005).
SEQ CHPTER \h
1Adams, S.A., Modayil, M.V., Daguise, V.G., Berger, S.H., Horner, M.-J.D., Teas, J., Brandt, H.M., Mitas, M., Mosley, C.M., Johnson, M.G., Cunningham, J.E., Butler, W.M., and Hebert, J.R. Breast Cancer Disparities in South Carolina: Early detection, Special Programs, and Descriptive Epidemiology. eJournal S.C. Med. Assoc. 101:e188-194 (2005
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