Project 1: Identify therapeutic target for ER-negative breast cancer using proteomic technology
African-American (AA) women have a distinct tumor phenotype characterized by negative estrogen (ER) status. As a result, the AA breast cancer is resistant to the existing targeted treatments such as tamoxifen and hormonal treatments. The mechanism underlying the resistance to the treatment is not well understood. The overall objective of this project is to understand the biological basis of breast cancer with ER negative phenotypic expression in order to identify alternative molecular targets for treatment

Project 2. 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.

Project 3. Idenification of the protein targets for ealier F BC development
We are interested in identifying key molecular changes and biological pathways in tumorigenesis as well as exploring the novel chemo-preventive and therapeutic strategies. Three complementary studies will be carried out in the proposed project (i) To evaluate targeted protein expression profiles for those cells with a (+/+) and (+/-) genotype for BRCA1 with the goal of identifying protein alterations in the BRCA1-DNA repair pathway that lead to the earlier development of breast cancer. (ii) To evaluate targeted protein expression profiles from these cells before and after PARP inhibitor treatment in vitro with the goal of suggesting whether PARP inhibitors will reverse those expression changes caused by BRCA1 defects. (iii) To compare in vitro protein expression profiles obtained in specific aims 1 and 2 and to identify proteins that might serve as good targets at protein level that are modulated by PARP inhibitors, and thus might be appropriate targets for the development of new chemo-preventive agents. 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.

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