The Role of Thromboxane A2 (TP) Receptor Beta in Bladder Cancer

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DESCRIPTION (provided by applicant): In the US, bladder cancer is the fourth most common cancer in men and the eighth most common cancer in women. Approximately 60,000 people develop bladder cancer each year. Unfortunately, recurrence, invasion, and metastasis, even after a seemingly successful treatment at a very early stage, are characteristic of bladder cancer. Studies directed towards elucidation of the factors involved in its progression should facilitate the design of molecularly based diagnostic and therapeutic approaches. Our preliminary data demonstrate that: (i) the thromboxane A2 (TP) beta receptor isoform uniquely is over-expressed in human bladder cancer and cell lines and over-expression is correlated with a poorer prognosis in patients; (ii) TP beta, but not TP alpha, receptor expression increases malignant phenotypes in vitro and produces a malignant transformation of immortalized bladder epithelial cells in vivo; (iii) TP receptor antagonists reduce bladder cancer cell growth, migration and invasion and inhibit tumor growth in vivo; and (iv) urinary TXB2 and TP beta receptor protein are significantly greater in bladder cancer patients compared to controls, supporting potential diagnostic and prognostic utility. Based upon our preliminary studies and published literature, we hypothesize that the increased expression of TP beta receptor and activation of its signaling pathways play a critical role in bladder cancer cell growth and metastases. To define the oncogenic potential of TP beta receptor signaling, we propose the following specific aims: 1: Determine the proximal mediators (G protein dependent and independent) of the signaling pathways coupled to the TP beta receptor isoform responsible for bladder cancer cell migration, invasion, and proliferation; 2. Determine the mechanism of the regulation by TP beta of the downstream effectors (tumor suppressor PTEN and pro-angiogenic pleiotrophin) responsible for its induced malignant phenotype and 3. Determine whether tissue expression of TXAS, TP beta receptor, urinary TXB2, urinary TP beta receptor, and down-stream effectors exhibit prognostic significance in the progression of human bladder cancer. The proposed studies utilize a combination of molecular and cellular techniques, mouse models when appropriate and clinical studies. These approaches provide a comprehensive analysis of possible tumor-related functions of TP beta receptor-signaling, and may identify a new therapeutic target for bladder cancer, and maybe other cancers. PUBLIC HEALTH RELEVANCE: Data presented in this research proposal indicate for the first time the association between thromboxane receptor 2 isoform expression and poor survival in bladder cancer patients. There is a strong probability that the proposed research will advance our knowledge in bladder cancer and there is a potential possibility that we can predict the disease progression from superficial to invasive based on the levels of thromboxane receptor 2 isoform and/or its down-stream effectors.