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Molecular Imaging of CXCR4 in Breast Cancer: Effects on Tumor Angiogenesis
Background: The chemokine SDF-1 (CXCL12) and its receptor CXCR4 appear to comprise a key signaling pathway in breast cancer and may be a new therapeutic target. Molecular imaging provides the unique opportunity to monitor dynamic changes in CXCL12/CXCR4 signal transduction in living animals. Receptor activation, protein-protein interactions in signaling pathways, and changes in gene expression can be quantified in vivo. Molecular imaging also enables us to measure effects of targeted molecular therapy in relationship to overall breast cancer progression. We will use our expertise in imaging protein interactions and signaling to study CXCL12/CXCR4 in the intact tumor microenvironment, focusing on CXCR4 in angiogenesis. Objective/hypothesis: We will investigate if CXCL12/CXCR4 signaling affects breast cancer progression and tumor angiogenesis in vivo. We hypothesize that CXCR4 activation and inhibition correlate with breast cancer growth, and that CXCR4 promotes tumor angiogenesis. Specific Aims: 1) To determine if inhibition of CXCR4 signaling limits primary and metastatic breast cancer in a mouse model, using molecular imaging to monitor CXCR4 activation. 2) To investigate if CXCR4 promotes angiogenesis in primary and metastatic breast tumors. Study Design: We will use murine 4T1 breast cancer cells, a well-established model of primary and metastatic breast cancer. Cells will be engineered with imaging reporters to detect activation and downstream signaling from CXCL12/CXCR4. Functions of CXCR4 in tumor angiogenesis will be monitored by imaging VEGF promoter activity, as wells as directly imaging blood vessels in primary and metastatic tumors. CXCR4 signaling will be blocked with a selective chemical antagonist to test if changes in CXCR4 signaling directly correlate with tumor progression and angiogenesis. Potential Outcomes and Benefits of Research: Molecular imaging will enable us to monitor CXCR4 signaling in living mice, providing an innovative approach to investigate CXCL12/CXCR4 in the intact tumor microenvironment. We will establish if therapeutic benefits of a CXCR4 inhibitor are directly related to reductions in CXCR4 signaling in tumor cells, validating CXCR4 as a key regulator of breast cancer. These studies may provide justification for testing CXCR4 antagonists as targeted therapy for patients with breast cancer.
Breast cancer initiation, growth of cancer cells in the breast, and metastatic spread of cancer cells to other organs are regulated by interactions between cancer cells and normal tissues in the tumor microenvironment. Most studies of breast cancer have focused only on isolated cancer cells, while effects of normal tissues on cancer cell signaling and growth have not been widely explored. Emerging data suggest that interactions between cancer and normal cells control multiple steps in breast cancer progression and may be important new targets for therapy. It is important to understand molecular events in breast cancer in a living animal, because signal activation changes when cancer cells are studied without normal cellular cues. Recent advances in imaging technology allow specific signals and molecules to be measured non-invasively in living mice, providing a unique opportunity to investigate dynamic interactions between breast cancer and normal cells in intact tumors. Our studies focus on signals produced by binding of the chemokine protein CXCL12 to its receptor CXCR4. CXCL12 is produced by normal cells in the breast and organs commonly affected by metastatic breast cancer, and it activates signals from the CXCR4 receptor expressed on many breast cancer cells. While CXCL12/CXCR4 appears to regulate breast cancer growth and metastases, little is known about activation of CXCR4 signals in breast cancer cells or specific steps in tumor progression that are regulated by CXCR4. We will use our expertise in non-invasive imaging techniques to investigate CXCR4 signaling in a mouse model of primary and metastatic breast cancer. We also will establish if CXCR4 signaling increases formation of new tumor blood vessels, an essential early step in tumor development. As an important step toward determining if CXCR4 represents a new target for breast cancer therapy, mice will be treated with a specific CXCR4 inhibitor, and specific effects on CXCR4 signaling, tumor blood vessels, and breast cancer progression will be quantified with imaging. This innovative approach will establish if effects on growth of tumor blood vessels and/or cancer cells are due to specifically blocking CXCR4 in breast cancer cells. Studying CXCL12/CXCR4 in the intact tumor microenvironment potentially will justify use of CXCR4 inhibitors, alone or in combination with other compounds, as a new therapeutic strategy to treat human breast cancer.