Our long-term goal is to understand the molecular mechanisms underlying tumor development and metastasis. This application focuses on studying Slit signaling in breast cancer. Slit gene family encodes secreted proteins guiding neuronal migration and inhibiting chemokine activation. Slit is the first reported chemokine inhibitor produced by cells. The observation that Slit is frequently inactivated in a range of tumors indicates a role of Slit gene in tumor suppression. We have established several assays and shown that Slit inhibits chemokine-induced invasion and migration of breast cancer cells in vitro. Our preliminary study suggests that Slit suppresses cancer metastasis in vivo. Our hypothesis, supported by the preliminary results, is that Slit signaling is important for inhibiting cancer metastasis. We plan to examine the role of Slit signaling in breast cancer invasion .and metastasis in vitro and in vivo. We will dissect the signal transduction pathways involved in Slit function in cancer cells. We have established assays and prepared reagents to investigate how Slit-signaling pathway communicates with chemokine signal transduction pathways. The proposed studies will provide new insights into mechanisms controlling tumor invasion and metastasis. Enhancing or activating the endogenous mechanisms that restrict or suppress cancer invasion/metastasis may likely provide novel approaches for treating metastatic diseases.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Woodhouse, Elizabeth
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Northwestern University at Chicago
Schools of Medicine
United States
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Brantley-Sieders, Dana M; Dunaway, Charlene M; Rao, Meghana et al. (2011) Angiocrine factors modulate tumor proliferation and motility through EphA2 repression of Slit2 tumor suppressor function in endothelium. Cancer Res 71:976-87
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Yang, Guang; Huang, Shu-Ching; Wu, Jane Y et al. (2008) Regulated Fox-2 isoform expression mediates protein 4.1R splicing during erythroid differentiation. Blood 111:392-401
Li, Xiaoling; Gao, Xue; Liu, Guofa et al. (2008) Netrin signal transduction and the guanine nucleotide exchange factor DOCK180 in attractive signaling. Nat Neurosci 11:28-35
Fushimi, Kazuo; Ray, Payal; Kar, Amar et al. (2008) Up-regulation of the proapoptotic caspase 2 splicing isoform by a candidate tumor suppressor, RBM5. Proc Natl Acad Sci U S A 105:15708-13

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