Abstract

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. ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA114197-03
Application #
7414829
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Woodhouse, Elizabeth
Project Start
2006-06-02
Project End
2011-03-31
Budget Start
2008-05-01
Budget End
2009-03-31
Support Year
3
Fiscal Year
2008
Total Cost
$258,250
Indirect Cost

  Institution

Name
Northwestern University at Chicago
Department
Neurology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611

  Publications

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
Dunaway, Charlene M; Hwang, Yoonha; Lindsley, Craig W et al. (2011) Cooperative signaling between Slit2 and Ephrin-A1 regulates a balance between angiogenesis and angiostasis. Mol Cell Biol 31:404-16
Kaneko, Naoko; Marín, Oscar; Koike, Masato et al. (2010) New neurons clear the path of astrocytic processes for their rapid migration in the adult brain. Neuron 67:213-23
Yu, J; Cao, Q; Yu, J et al. (2010) The neuronal repellent SLIT2 is a target for repression by EZH2 in prostate cancer. Oncogene 29:5370-80
Yuasa-Kawada, Junichi; Kinoshita-Kawada, Mariko; Wu, Guan et al. (2009) Midline crossing and Slit responsiveness of commissural axons require USP33. Nat Neurosci 12:1087-9
Yuasa-Kawada, Junichi; Kinoshita-Kawada, Mariko; Rao, Yi et al. (2009) Deubiquitinating enzyme USP33/VDU1 is required for Slit signaling in inhibiting breast cancer cell migration. Proc Natl Acad Sci U S A 106:14530-5
Liu, Guofa; Li, Weiquan; Wang, Lei et al. (2009) DSCAM functions as a netrin receptor in commissural axon pathfinding. Proc Natl Acad Sci U S A 106:2951-6
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

Showing the most recent 10 out of 54 publications