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    Awarded Grants
    TWEAK: A New Molecular Target for Breast Cancer Therapy?

    Scientific Abstract:
    Background: Breast cancer is the second-leading cause of cancer-related death among women in the United States. Primary breast tumor growth is dependent on new blood vessel formation (angiogenesis) and these new microvessels also provide a gateway for tumor cell metastasis. Breast cancer cells frequently metastasize to bone and in most cases this results in osteoclast-mediated bone resorption (osteolysis), which can lead to bone pain and fractures. We are studying a member of the TNF superfamily named TWEAK that acts via binding to a cell surface receptor named Fn14. Our initial studies have revealed that both primary breast tumors and invasive breast cancer cells cultured in vitro express TWEAK and Fn14 and that TWEAK is a potent angiogenic factor and osteoclast cell differentiation factor. Objective/Hypothesis: We hypothesize that the TWEAK-Fn14 signaling system may regulate multiple phases of breast cancer progression, including primary tumor growth, angiogenesis, tumor cell invasion, and tumor cell-stimulated bone destruction. The objective of this project is to test this novel hypothesis utilizing both in vitro and in vivo assays. Specific Aims/Study Design: (1) To generate stably-transfected human breast cancer cell lines that express either low or high levels of the TWEAK cytokine, (2) To determine whether TWEAK-expressing breast cancer cell lines have enhanced proliferation, migration or invasion capacity in vitro, and (3) To determine whether TWEAK-expressing breast cancer cell lines have enhanced tumorigenic, angiogenic, metastatic or osteolytic activity in immunodeficient mice. Potential Outcomes/Benefits of the Research: The proposed research should indicate whether breast tumor cell-derived TWEAK is able to stimulate breast tumor angiogenesis, growth, metastasis and/or osteolysis. If this is indeed the case, then the TWEAK-Fn14 cytokine-receptor system will be identified as a new molecular pathway that could be targeted for therapeutic inhibition of human breast cancer.

    Lay Abstract:
    Background: Breast cancer is a complex disease characterized by accelerated cell growth, primary tumor vascularization, tumor cell invasion into the patient’s circulatory/lymphatic system, and the development of metastatic lesions in other organ systems, including bone. Our lab is studying a protein named TWEAK that stimulates cellular responses by binding to a cell surface receptor named Fn14. We recently discovered that both invasive breast cancer cell lines and primary breast tumors express the TWEAK protein. In addition, we found that TWEAK can stimulate blood vessel formation (angiogenesis), a process critical for breast tumor growth and metastasis, and promote the differentiation of osteoclasts, which are the cells within bone marrow involved in breast cancer cell-mediated bone destruction (osteolysis). Objective/Hypothesis: We hypothesize that breast tumor cell-derived TWEAK may be involved in several different phases of breast cancer development (tumor growth, cell invasion, metastasis, osteolysis). The overall goal of this project is to test this hypothesis by examining the properties of breast cancer cell lines that express either low or high levels of TWEAK. Specific Aims/Study Design: We propose three specific aims in this application to test our hypothesis. Briefly, we intend to manipulate TWEAK expression levels in two different human breast cancer cell lines and then compare the growth, invasion, and osteolytic properties of these cells using in vitro and in vivo assays. Potential Outcomes/Benefits of the Research: This innovative research project addresses several aspects of breast tumor biology that directly impact on disease progression and the quality of life for breast cancer patients. If we find that TWEAK can promote tumor growth, angiogenesis, metastasis and/or bone destruction then this study will have in fact identified new molecules (TWEAK, Fn14) that could potentially be targeted for therapeutic inhibition of breast cancer.