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    Research Grants Awarded

    Osteoblastic Egfr Signaling In Breast Cancer Bone Metastasis

    Grant Mechanism:
    Career Catalyst Research

    Scientific Abstract:
    Bone metastasis occurs in greater than 80% of breast cancer patients with advanced disease. The metastasized tumors stimulate bone destruction by activating osteoclasts and inhibiting osteoblasts, resulting in an increase in morbidity and mortality in breast cancer patients. The epidermal growth factor (EGF)-like ligands and their cognate receptors play prominent roles in the pathogenesis of human carcinoma. Recent studies in my laboratory revealed that EGF-like ligands have dual actions on bone metabolism through activation of osteoblastic EGF receptor (EGFR) signaling pathways. On the one hand, these ligands strongly inhibit osteoblast differentiation and mineralization. On the other hand, they regulate the expression of two secreted osteoclast regulatory factors (OPG and MCP1) by osteoblasts, therefore indirectly stimulating osteoclast formation and bone destruction. Further experiments found that coculture with a bone metastatic breast cancer MDA-MB-231 cells had similar effects on the expression of OPG and MCP1 in osteoblastic cells and these effects could be partially abolished by the EGFR inhibitor PD153035, suggesting that breast cancer cells use EGF-like ligands to stimulate osteoclastogenesis by acting on osteoblasts. Since a high percentage of human breast cancer cells express EGF-like ligands, I hypothesize that tumor-derived EGF-like ligands contribute to breast cancer-induced osteolytic bone lesions by suppressing bone formation and stimulating bone resorption. Thus the goal of this application is to delineate the role of osteoblastic EGFR signaling in breast cancer metastasis. To test this hypothesis, I will first construct breast cancer cell lines with EGF-like ligands either overexpressed or deleted and examined their effects on osteoblasts and osteoclasts in vitro. Then, I will study whether manipulating expression of EGF-like ligands in breast cancer cells will result in an alteration of cancer cell bone metastasis using mouse models. Lastly, I will delineate the molecular mechanisms of how EGF-like ligands suppress Runx2 activity and subsequently regulate expression of bone marker genes and osteoclast regulatory factors by osteoblasts. Since current therapies remain only palliative for advanced metastatic breast cancer patients, our research will shed light on a novel mechanism mediating breast cancer bone metastasis and indicate new therapies directly targeting bone metastasis given the availability of anti-EGFR treatments.

    Lay Abstract:
    Most breast cancer patients at later stage have aching bones and fractures because their cancer cells spread to bone and eat away healthy bone. This causes great discomfort and increasing death in breast cancer patients. In normal bone, a balance is normally maintained between the breaking down and building up of bone. Once breast cancer cells ?set up house? in bone, they stimulate bone break down and inhibit bone build up, causing weak spots, where the bones can break easily. I have identified that a family of growth factors, epidermal growth factor (EGF)-like proteins, are present in breast cancer cells and these proteins have similar effects on bone as breast cancer cells. I hypothesize that cancer cell utilize these factors to destroy health bones. To prove it, I will create breast cancer cell lines that produce large amounts of EGF-like proteins and inject these cells into mice to see whether these cells cause greater bone destruction. I will also create breast cancer cells that no longer produce these factors and inject these cells into mice to see whether the bone destruction is alleviated. Moreover, I will study why these factors have such effects on bone balance. This research will help us understand the mechanism of how breast cancer cells destroy bone and open up new possibilities to develop new treatments or modify current treatments for breast cancer patients.