) The main objective of our proposal focuses on the continued characterization of mutations and altered patterns of expression of cell cycle regulators as they relate to processes of tumorigenesis and tumor progression in bladder cancer. It is our hypothesis that molecular abnormalities of TP53 and RB genes, as well as those that directly or indirectly affect their encoded products, produce a selective advantage for tumor growth and an aggressive behavior in bladder cancer patients. This is supported by the facts that TP53 mutations and altered expression of p53 and pRB are frequent events in bladder tumors and are associated with poor clinical outcome and reduced patient survival. Recently, deletions at 9p2l, affecting pl6 and pl5, have been documented to occur in bladder tumors and were associated with superficial lesions. In addition, certain cyclins and cyclin- dependent kinases have been shown to become activated oncogenes in a subset of cancers. Identification of these alterations may in turn reveal their important clinical value as tumor markers for the early detection and monitoring of patients affected with bladder cancer, as well as in predicting tumor behavior. The goals of our program are to translate basic research findings into clinical studies, and to collaborate with the Network laboratories and NCI representatives in the evaluation of tumor markers recommended by the Coordinating Committee.
The Specific Aims are outlined as follows:
Aim #1 : Molecular and Functional Analyses of TP53 and RB in Superficial and Invasive Bladder Cancer. We plan to prospectively validate previous reports from our laboratory and other groups that showed the prognostic value of TP53 and RB. We will also study down- stream events of their pathways, including mdm2 and E2F proteins. Furthermore, functional studies of p53 and pRB will be conducted to distinguish silent mutations from those contributing to the malignant phenotype.
Aim #2 : Characterization of Cyclin-Dependent Kinase Inhibitory (CKI) Gene Mutations in Bladder Cancer. Due to the recessive nature of this new family of negative regulators, it has been suggested that they function as suppressor genes. Reports from our group and other coinvestigators revealed that certain CKI genes (mainly pl6 and pl5) are mutated in bladder tumors. We propose to determine if their inactivation is an early and frequent event in bladder tumors. Furthermore, we will test if reintroduction of wild type genes can revert the tumorigenic phenotype of bladder cancer cells. Targeted disruption of these genes will further disclose their role in development and tumorigenesis.
Aim #3 : Immunophenotypic and Molecular Studies of Cyclins and Cyclin- Dependent Kinases in Bladder Cancer. We have assembled a well characterized panel of probes to specific cyclins and Cdks and plan to determine if detection of abnormal patterns of expression are of clinicopathological consequences, suggesting that their identification is of prognostic value.
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