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Role of Cyr61(CCN1) in Breast Cancer Tumor Progression
Tumor Cell Biology VI
Cyr61 contains four modular domains with homology to 1) insulin-like growth factor-binding proteins (IGFBP), 2) von Willebrand factor (VWF), 3) thrombospondin (TSP1), and a 4) heparin-binding growth factor C-terminal domain (HepCT). Therefore, the multimodular structure of these proteins raises interesting questions about their normal biological roles in cell adhesion, migration, proliferation, and angiogenesis and potential pathological roles in tumor growth, invasion and metastasis. Matrix metalloproteases (MMPs) play a central role in remodeling the tumor-stromal microenvironment. We recently determined that stromal-derived MMP-1 also acts as a signaling molecule by cleaving protease-activated receptor 1 (PAR1) to cause breast cancer cell migration and invasion. The tumor-derived Cyr61 acts as an invasogenic signaling molecule that induces MMP-1 expression in adjacent stromal fibroblasts. Gene silencing of Cyr61 in breast cancer cells suppresses MMP-1 induction in stromal fibroblasts resulting in a major loss in migration of the cancer cells towards the fibroblasts. We hypothesize that the angiogenic factor Cyr61(CCN1) is a critical regulator of cancer-stromal communication, angiogenesis, invasion and metastasis by regulating MMP and chemokine expression. We propose that Cyr61 promotes tumorigenesis on tumor vs stromal cells through diverse surface receptors that control expression of MMP essential for cancer cell invasion and chemokines that control endothelial cell chemotaxis and vessel formation during tumor progression. This proposal will examine molecular roles of the four structurally conserved domains of Cyr61 in angiogenesis using in vivo matrigel plug assay.
The highly complex mechanism of cancer cell-stromal cell MMP- and chemokine-regulation is not well understood and identification of the factors that mediate this complex process may enable the development of novel therapeutics that target the invasive and metastatic phase of cancer?important goals of aims 1 and 2. Here, we show that the tumor-derived Cyr61 acts as an invasogenic signaling molecule that induces MMP-1 expression in adjacent stromal fibroblasts. Moreover, preliminary evaluation using gene silencing of Cyr61 in breast cancer cells reveals suppression of expression of major MMPs essential for invasion of breast cancer cells. We have identified a novel conserved domain of Cyr61 as essential domain in mediating migration of breast cancer cells. Future experiments are proposed in aim 1 that will study mechanism of cancer cell-stromal cell MMP- and chemokine-regulation. Aim 2 will develop novel inhibitors against Cyr61 that holds potential to differentially target tumor vs stromal functions of Cyr61. Moreover, downstream effector molecules of MMP-1 and chemokine targets (G-protein coupled receptors) will be inhibited using novel pepducin technology. Overall goal is to interrupt tumor-stromal cell communication by targeting Cyr61and its downstream effectors, which may provide an alternative therapeutic approach for the treatment of invasive breast cancer.