The overall goal of this project is to explore new strategies for more effective treatment of breast carcinoma and multiple myeloma based on modulating signal transduction pathways. Signal transducers and activators of transcription (STATs) are transcription factors that were discovered as key signaling components involved in mediating responses to cytokine stimulation. More recently, evidence has been accumulating that points to the involvement of STAT proteins in oncogenesis. We previously made the original observations that one STAT family member, STAT3 is constitutively activated in fibroblast cell lines transformed by the Src oncoprotein and is required for cell transformation. In addition, STAT3 is constitutively activated in fibroblast cell lines transformed by the Src oncoprotein and is required for cell transformation. In addition, STAT3 signaling is constitutively activate din fibroblast cell lines transformed by the Src oncoprotein and is required for cell transformation. In addition, STAT3 signaling is constitutively activated with high frequency in cell lines and tumor specimens of patients with breast cancer as well as the blood malignancy, multiple myeloma. We have shown that STAT3 signaling confers resistance in apoptosis in human myeloma tumor cells, providing evidence that STAT3 participates in malignant progression of this tumor by preventing programmed cell death. Moreover, another consequence of this anti-apoptotic activity of STAT3 may be to confer resistance to chemotherapy. In this project, we propose to test the hypothesis that STAT3 signaling participates in malignant progression of human cancer through regulation that also induce resistance to chemotherapy. This goal will be pursued through the following specific aims: (1) To define the mechanisms by which activated STAT3 signaling contributes to malignant transformation of breast carcinoma cells. (3) To determine if increasing levels of STAT3 activation are associated with malignant progression of multiple myeloma and acquisition of chemotherapy resistant in patients. (4) To develop new therapies for breast carcinoma and multiple myeloma based on pharmacologic approaches to inhibiting STAT3 signaling in animal models. In later years of this project, the basic mechanistic studies and clinical studies will be extended to ovarian cancer and acute myelogenous leukemia in order to assess the generality of our findings. Results of these studies will further define the role of activated STAT signaling in oncogenesis and evaluated new strategies for more effective therapy of human cancers that harbor activated STAT proteins.
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