Prostate cancer is the second cause of cancer deaths in men in the United States. Local invasion of prostate by cancer cells as well as the spread to regional lymph nodes are the key factors related to poor prognosis. Advanced metastatic prostate cancer is currently not curable. Significant attention was devoted to the role of male steroid hormones in cancer progression. However, after advancing to the androgen-independent stage, prostate cancer becomes unresponsive to androgen ablation therapy. Therefore, identification of novel endogenous factors responsible for proliferation, survival, and migration of the prostate cancer cells may create potential therapeutic targets for treatment. The key aim of this project is to demonstrate the significance of relaxin (RLN) signaling in progression of prostate cancer. Recent experimental data obtained in our laboratory and others indicate that RLN stimulates increase in prostate carcinoma cell invasiveness and proliferation in vitro and in vivo. The suppression of endogenous RLN or its receptor LGR7 expression in cancer cells by siRNA drastically reduced an invasive phenotype and increased apoptosis of cancer cells in vitro. We have established that the RNA expression of LGR7 is maintained at different stages of prostate cancer, whereas the expression of RLN is increased in human cancer samples, and especially in recurrent cancers. The transgenic overexpression of RLN in mice decreased the survival, increased the rate of metastasis, and decreased cancer cell apoptosis in TRAMP mouse prostate cancer model. It was reported that RLN directly mediates p53-dependent increase in androgen-independent growth of prostate cells. The main hypothesis of the proposal is that the inhibition of relaxin signaling can reduce the progression of prostate cancer in vivo. The hypothesis will be tested by the following specific aims:
Specific Aim 1. Determine whether ablation of RLN signaling affects tumorigenesis and metastatic potentials of mouse transgenic adenocarcinoma of prostate (TRAMP) in vivo. Analyze the mechanisms of RLN action in this model.
Specific Aim 2. Determine whether the suppression of RLN signaling affects growth, invasiveness, and metastasis in an orthotopic model of human prostate cancer progression. Demonstration of the anti- tumor activity of RLN signaling suppression may provide a novel target for therapeutical intervention in this deadly disease. ? ? ?
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