Growth factors modulate cell proliferation, migration, and survival. Precise regulation of these processes is critical as deregulated growth factor signaling increases cellular migration and drives tumor invasion and metastasis, the major cause of cancer-related deaths. Although Abl nonreceptor tyrosine kinases initiate leukemia development, their role in the development or progression of solid tumors has not been studied. Previously, we showed that Abl kinases are activated downstream of growth factor receptors via Src family kinases and PLC-yl, and influence growth factor-mediated cytoskeletal reorganization and migration in fibroblasts. Deregulation of growth factor receptors, Src kinases and PLC-yl in solid tumors, such as breast cancer, drives tumor invasion and metastasis. Our studies demonstrate that the Abl kinases are dramatically activated downstream of activated growth factor receptors and Src kinases in highly aggressive breast cancer cell lines, and promote breast cancer invasion. Based on these findings, the overall objective of this proposal is to characterize the conditions leading to Abl kinase activation in breast cancer, and to define invasion-promoting signaling cascades controlled by the Abl kinases. We hypothesize that Abl family kinases translate and direct growth factor receptor and Src kinase-mediated signals to influence breast cancer invasion and metastasis.
Three Specific Aims are described to evaluate this hypothesis: 1) Determine the conditions that activate the Abl kinases in breast cancer;2) Identify biological and molecular mechanisms by which Abl kinases promote breast cancer cell invasion;and 3) Determine whether activation of the Abl kinases promotes breast cancer metastasis, in vivo. To achieve our goal, we will combine biochemical, molecular, cellular, and whole animal approaches using: 1) primary breast tissue, breast cancer cell lines;RNAi, and inhibitors to identify mechanisms and conditions of Abl activation;2) RNAi, chemotaxis, invasion, and zymography assays to identify mechanisms by which Abl kinases promote invasion;and 3) in vivo metastasis studies to assess whether activation of the Abl kinases promotes metastasis in immune- compromised mice. These data are likely to provide mechanistic insight into how abnormal regulation of the Abl kinases contributes to breast cancer progression, which may aid in the discovery of new drug combinations for preventing breast cancer metastasis and decreasing mortality.
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