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.
|Elbaz, Mohamad; Ahirwar, Dinesh; Xiaoli, Zhang et al. (2018) TRPV2 is a novel biomarker and therapeutic target in triple negative breast cancer. Oncotarget 9:33459-33470|
|Ahirwar, Dinesh K; Nasser, Mohd W; Ouseph, Madhu M et al. (2018) Fibroblast-derived CXCL12 promotes breast cancer metastasis by facilitating tumor cell intravasation. Oncogene 37:4428-4442|
|Elbaz, Mohamad; Ahirwar, Dinesh; Ravi, Janani et al. (2017) Novel role of cannabinoid receptor 2 in inhibiting EGF/EGFR and IGF-I/IGF-IR pathways in breast cancer. Oncotarget 8:29668-29678|
|Zhao, Helong; Ahirwar, Dinesh K; Oghumu, Steve et al. (2016) Endothelial Robo4 suppresses breast cancer growth and metastasis through regulation of tumor angiogenesis. Mol Oncol 10:272-81|
|Nasser, Mohd W; Wani, Nissar Ahmad; Ahirwar, Dinesh K et al. (2015) RAGE mediates S100A7-induced breast cancer growth and metastasis by modulating the tumor microenvironment. Cancer Res 75:974-85|
|Elbaz, Mohamad; Nasser, Mohd W; Ravi, Janani et al. (2015) Modulation of the tumor microenvironment and inhibition of EGF/EGFR pathway: novel anti-tumor mechanisms of Cannabidiol in breast cancer. Mol Oncol 9:906-19|
|Ahirwar, Dinesh K; Nasser, Mohd W; Jones, Travis H et al. (2015) Non-contact method for directing electrotaxis. Sci Rep 5:11005|
|Zhao, Helong; Wilkie, Tasha; Deol, Yadwinder et al. (2015) miR-29b defines the pro-/anti-proliferative effects of S100A7 in breast cancer. Mol Cancer 14:11|
|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|
|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|
Showing the most recent 10 out of 28 publications