The management of prostate cancer has several major challenges. First, there are currently no effective treatments for hormone-refractory or metastatic prostate cancer. Second, there is a lack of reliable prognostic markers that would identify low/intermediate-grade prostate cancers that are likely to progress to aggressive metastatic disease. We have recently established transcription factor Stat5a/b as a critical protein for survival of human prostate cancer cells. Stat5a/b is the key signaling protein in prostate that mediates the effects of prolactin (Prl) which is a powerful mitogen and survival factor for prostate epithelium and is locally produced by both normal and malignant prostate cells. Our recent data show that transcription factor Stat5a+b is constitutively activated in human prostate cancer but not in adjacent normal epithelium, and that activation of Stat5a+b and expression of Prl protein strongly associate with high histological grade of prostate cancer. Moreover, our preliminary data suggest that Stat5a/b is involved in progression of human prostate cancer to hormone-refractory and metastatic disease. Here, we propose to mechanistically test the central hypothesis: ?As a result of elevated activity of Prl-Jak2-Stat5a/b signaling pathway in prostate cancer, activation of Stat5a/b stimulates growth and metastasis of human prostate cancer?. We propose to pursue three specific aims:1: Determine upstream mechanisms of constitutive Stat5a and/or 5b activation in human prostate cancer. 2: Determine whether active Stat5a and/or 5b inhibits homotypic adhesion of human prostate cancer cells and stimulates heterotypic adhesion, motility and invasion of prostate cancer cells, in vitro and in vivo. 3: Determine the prognostic values of Stat5a and Stat5b in human prostate cancer with disease recurrence as endpoint. At the completion of this work, we expect to have determined the mechanisms underlying constitutive activation of Stat5a/b in prostate cancer. Moreover, we expect to have established whether Stat5a/b promotes invasion and metastasis of human prostate cancer cells. Finally, we will have determined whether active Stat5a and/or Stat5b can be used as a tumor biomarker for prostate cancers that are likely to recur early. More individualized therapy may be of direct benefit to prostate cancer patients.
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