SUMMARY OF CURRENT RESEARCH PROJECTS

Project 1. Exploring the novel chemo-preventive strategies using human mutant cells from Familial Breast Cancer.

Inherited alterations in the genes called BRCA1 and BRCA2 are involved in many cases of Familial Breast Cancer. Women with a BRCA1 or BRCA2 alteration are much more likely than other women to develop breast or ovarian cancer. Importantly, the study of BRCA1/2's role in normal cell chromosomal DNA repair pathways has provided great insight into how defects in these repair mechanisms underlie cancer progression. Notably, recent studies have shown that inhibitors of poly (ADP-ribose) polymerase (PARP), a key DNA repair enzyme, exhibits significantly enhanced toxicity to BRCA1- or 2-deficient cells, and clinical trials have been initiated in patients with BRCA deficiency. Therefore, PARP may have the potential to block, reverse, or delay early stages of Familial Breast Cancer.

We are interested in identifying key molecular changes and biological pathways in tumorigenesis as well as exploring the novel chemo-preventive and therapeutic strategies. We will employ proteomic technology to evaluate protein expression levels of cells harboring heterozygotes for BRCA1 mutation with controls in the presence and absence of the PARP inhibitor. This will allow us to gain insight into the mechanism by which PARP inhibitors function and to evaluate in vitro pharmacology of PARP as a chemo-preventive agent.

Project 2: Identifying molecular markers between breast cancer cells from African American and Caucasian women.

African American (AA) women have a lower overall incidence of breast cancer than do Caucasian (CAU) women, but a higher overall mortality. Little is known as to why the incidence of breast cancer is lower yet mortality is higher in AA women. Many studies speculate that this is only a socio-economical problem. This proposed project will study the molecular mechanisms contribute to the increased mortality of AA women with breast cancer. The effort is to highlight genetic differences that are related to ethnicity. Cell lines derived from AA and CAU patients will be analyzed to demonstrate alterations in the proteins from AA and CAU women. Total protein will be extracted from cell lines and analyzed by 2D proteomics. An in vitro comparison of the protein expression between AA and CAU cell lines will be evaluated. Results from this study will provide the lead that altered expression of the proteins may play a role in the phenotype seen in breast cancer in African American women.

Project 3. The molecular mechanism controlling Srx and PrxII interaction.

A major goal of this task is to shed light on the Sufiredoxin (Srx) - (peroxiredoxinII) PrxII interaction, which to date is only poorly understood. The peroxiredoxin family of proteins is an evolutionarily conserved group of antioxidants that protect cells from oxidative damage by catalyzing the reduction of a wide range of cellular peroxides. There is evidence suggesting that the PrxII levels are a major factor in clinical radiosensitivity of tumors, and that modulation of PrxII or its regulators will impact therapeutic outcomes in a significant way. Sufiredoxins repair the inactivated forms of typical two-Cys peroxiredoxins. The biochemistry and structure organization of Srx and PrxII have been intensively investigated, but little information is available for specific functional interaction between this two proteins. We propose to determine critical sites for specific interactions between Srx and PrxII using site-directed mutagenesis to alter specific amino acid residues implicated as candidates for specific binding interactions. Candidate sites will include amino acids identifies previously as critical residues by chemical modification, residues showing significant interspecies conservation, and residues clustered in probable solvent exposed locations. This proposed study is our efforts to discern the molecular basis for the novel sulfur chemistry of Srx and its interactions with PrxII.

Tilly Wang, Ph.D. Assistant Professor, Chemistry Office: NSM B 304 Phone: (310) 243-3388 Email: twang@csudh.edu