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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA109527-07A1
Application #
8767126
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Jhappan, Chamelli
Project Start
2004-07-01
Project End
2019-07-31
Budget Start
2014-08-06
Budget End
2015-07-31
Support Year
7
Fiscal Year
2014
Total Cost
$242,550
Indirect Cost
$85,050
Name
Ohio State University
Department
Pathology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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
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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
Lu, Yuanzhi; Wu, Yongsheng; Feng, Xiaoling et al. (2014) CDK4 deficiency promotes genomic instability and enhances Myc-driven lymphomagenesis. J Clin Invest 124:1672-84
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

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