The roles of NRG1 and JAG1 in breast cancer transendothelial migration and intravasation
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The purpose of our studies is to investigate the role of Neuregulin1 (NRG1) and ErbB3 signaling between breast cancer cells and macrophages in facilitating tumor cell intravasation. The interaction of breast cancer cells with other cell types within the tumor microenvironment plays an important role in metastasis. These interactions are thought to influence tumor cell invasion and intravasation, two important steps in the process of metastasis. Our studies are specifically interested in examining the signaling occurring between tumor cells and macrophages. Previous studies have established the presence of paracrine signaling between breast cancer cells and macrophages, where colony stimulating factor 1 (CSF-1) produced by the tumor cells stimulates the production of epidermal growth factor (EGF) by macrophages, leading to chemotactic invasion of the tumor cells. In addition to this paracrine loop signaling between tumor cells and macrophages, it has been seen that macrophage expression of ErbB3, a member of the EGFR family of receptor tyrosine kinases, may play a role in facilitating tumor cell invasion.;In order to examine the effects of signaling between tumor cells and macrophages in intravasation, we utilize an in vitro transendothelial migration (iTEM) assay. This assay uses transwells coated with matrigel and endothelial cells in order to mimic the entry of tumor cells into blood vessels. We show that using an ErbB3 blocking antibody results in a significant reduction of macrophage-induced transendothelial migration of breast cancer cells. Additionally, reduction of expression of the ErbB3 receptor ligand Neuregulin1 in tumor cells using shRNA yields a similar result. These breast cancer cells expressing NRG1 shRNA also show a significant reduction in intravasation when injected orthotopically in mice. Stimulation of macrophages with NRG1 leads to increased expression of Jagged1 (JAG1), a ligand of the Notch receptor. Activation of the Notch receptor pathway has been shown to be involved in tumor cell invasion. Knockout of JAG1 in macrophages leads to a significant decrease in macrophage induced transendothelial migration.;Overall our studies look to further examine the interaction between tumor cells and macrophages, and these observations indicate that ErbB3, NRG1, and JAG1 could all serve as novel targets in metastasis and the tumor microenvironment.