Chemokine receptor CXCR4 and its cognate ligand CXCL12 have been shown to play important roles in the growth, invasion, and metastasis of breast cancer. Given that metastasis is the major cause of increased morbidity and eventual mortality in breast cancer patients, understanding how signaling molecules modulate the tumor microenvironment that leads to metastasis is of fundamental importance. CXCL12 has been shown to be produced by fibroblasts. Recently, we generated a novel CXCL12 floxed mouse model. Using these mice, we will further analyze the role of stromal CXCL12 in breast cancer progression, angiogenesis, and metastasis. CXCL12 has also been shown to bind to CXCR7. We and others have shown that the CXCL12/CXCR7 pathway plays an important role in enhancing tumor growth and metastasis. In addition, we and others have recently shown that the Slit2/Robo1 pathway possesses tumor suppressive activity through modulation of CXCL12/CXCR4 functional effects. In this proposal, we will further analyze the crosstalk between Slit2/Robo1 and CXCL12/CXCR4/CXCR7 signaling that modulates breast cancer growth, angiogenesis, and metastasis. In addition, we will use an innovative multi-disciplinary approach to analyze the molecular mechanisms by which Slit2/Robo1 inhibits tumor growth and angiogenesis through modulation of the tumor microenvironment. Finally, we will determine the therapeutic potential of Slit2/Robo1 and CXCL12/CXCR4/CXCR7 in breast cancer. Insight gained from these studies will help in developing novel and innovative therapeutic strategies for highly aggressive and metastatic breast cancers, especially triple-negative breast cancer.
CXCL12/CXCR4/CXCR7 and Slit2/Robo1 pathways have been shown to play important roles in breast cancer progression and metastasis. However, not much is known about the crosstalk and molecular mechanisms by which these molecules modulate breast cancer growth and metastasis. Using novel conditional knockout mice and soluble proteins, we will further characterize the role of these proteins in regulating breast tumo growth, angiogenesis and metastasis. These studies provide novel insights into the treatment of aggressive and metastatic breast cancers, which is the major cause of mortality in breast cancer patients, especially triple- negative breast cancers.
|Oghumu, Steve; Varikuti, Sanjay; Terrazas, Cesar et al. (2014) CXCR3 deficiency enhances tumor progression by promoting macrophage M2 polarization in a murine breast cancer model. Immunology 143:109-19|
|Wani, Nissar; Nasser, Mohd W; Ahirwar, Dinesh K et al. (2014) C-X-C motif chemokine 12/C-X-C chemokine receptor type 7 signaling regulates breast cancer growth and metastasis by modulating the tumor microenvironment. Breast Cancer Res 16:R54|
|Zhao, Helong; Anand, Appakkudal R; Ganju, Ramesh K (2014) Slit2-Robo4 pathway modulates lipopolysaccharide-induced endothelial inflammation and its expression is dysregulated during endotoxemia. J Immunol 192:385-93|
|Sneh, Amita; Deol, Yadwinder S; Ganju, Akaansha et al. (2013) Differential role of psoriasin (S100A7) in estrogen receptor * positive and negative breast cancer cells occur through actin remodeling. Breast Cancer Res Treat 138:727-39|
|Nasser, Mohd W; Qamri, Zahida; Deol, Yadwinder S et al. (2012) S100A7 enhances mammary tumorigenesis through upregulation of inflammatory pathways. Cancer Res 72:604-15|
|Tamama, Kenichi; Kawasaki, Haruhisa; Kerpedjieva, Svetoslava S et al. (2011) Differential roles of hypoxia inducible factor subunits in multipotential stromal cells under hypoxic condition. J Cell Biochem 112:804-17|
|Feng, Xiaoling; Wu, Zhaojia; Wu, Yongsheng et al. (2011) Cdc25A regulates matrix metalloprotease 1 through Foxo1 and mediates metastasis of breast cancer cells. Mol Cell Biol 31:3457-71|
|Preet, Anju; Qamri, Zahida; Nasser, Mohd W et al. (2011) Cannabinoid receptors, CB1 and CB2, as novel targets for inhibition of non-small cell lung cancer growth and metastasis. Cancer Prev Res (Phila) 4:65-75|
|Nasser, Mohd W; Qamri, Zahida; Deol, Yadwinder S et al. (2011) Crosstalk between chemokine receptor CXCR4 and cannabinoid receptor CB2 in modulating breast cancer growth and invasion. PLoS One 6:e23901|
|Deol, Yadwinder S; Nasser, Mohd W; Yu, Lianbo et al. (2011) Tumor-suppressive effects of psoriasin (S100A7) are mediated through the ýý-catenin/T cell factor 4 protein pathway in estrogen receptor-positive breast cancer cells. J Biol Chem 286:44845-54|
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