These studies focus on two topics: ovarian cancer and the Wnt pathway in human cancers. Ovarian cancer is the fifth most common cancer and the fourth leading cause of cancer death among women in the United States. Because of a lack of powerful screening and diagnostic tests, early detection has been difficult. Moreover, the molecular mechanisms important in ovarian cancer initiation, progression and resistance to chemotherapeutic drugs remain largely unknown. We are using SAGE and other state-of-the-art molecular techniques to identify tumor markers and gain a greater understanding of the molecular pathways involved in ovarian tumorigenesis and cisplatin resistance. Indeed, the analysis of gene expression in ovarian cancer suggests the involvement many novel pathways in this disease. We are currently investigating the roles of the different pathways using molecular and cellular approaches. Our ultimate goal is the development of mechanism-based interventions for ovarian cancer patients. For example, we have recently found an important role for extracellular matrix (ECM) remodeling in the development of drug resistance in ovarian cancer. Inhibition of ECM-cancer cell interactions may therefore provide novel therapeutic opportunities for the development of strategies to circumvent the problem of drug resistance in ovarian cancer. The Wnt pathway, which was originally defined as a crucial pathway for body patterning during fruit fly development, has recently been implicated in human cancer. APC, a gene mutated in 80% of all colon cancers, is involved in the downregulation of the Wnt pathway. Moreover, colon tumors containing wild-type APC, frequently contain activating mutations in other members of the pathway emphasizing its importance for colon cancer progression. We are developing inducible systems that may be useful in the identification of downstream transcriptional targets as well as upstream regulatory components of the pathway.
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