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    Research Grants Awarded

    Role Of CD1D1 In Breast Cancer Bone Metastasis

    Study Section:
    Tumor Cell Biology IV

    Scientific Abstract:
    SCIENTIFIC ABSTRACT: Bone metastasis is the most frequently found metastasis in breast cancer patients. Despite its importance, limited progress has been made in this research field. To study breast cancer bone metastasis, my laboratory has recently developed a syngeneic mouse model of breast cancer bone metastasis. Mouse mammary tumor TM40D-MB cells were implanted to mammary fat pad of Balb/c mice. Tumors developed in the mammary fat pads and became metastatic to the bone with an efficiency of 53%. From this metastasis model, we isolated a sub-population of breast tumor cells with a high potential for bone metastasis. The gene expression profile of these cells has been compared with that of breast cancer cells with lower metastatic potential using Affymetrix microarray analysis. Candidate molecular signature genes of breast cancer cells with a high potential for bone metastasis have been identified. One of the genes, CD1D1, was identified as a candidate involved in immune response and surveillance, whose down-regulation may be important for breast tumor bone metastasis. Objective/Hypothesis: In order for tumor cells to survive and metastasize to a secondary site such as bone, they use several mechanisms to evade from immune surveillance and to co-exist with the host immune system. One immune response involves natural killer T (NKT) cell, a unique lineage of lymphoid in the organism, to fight against tumor cell growth and metastasis. To the present, no study has linked CD1D-mediated anti-tumor immune response in breast cancer progression and bone metastasis. We hypothesize that breast tumor cells may need to disguise themselves to avoid NKT cell-mediated attack in bone host. We anticipate that in order for breast tumor cells to be able to escape from the immune surveillance and stay alive in bone environment with high amounts of NKT cells, they have to disrupt the CD1D1 mediated antigen presentation on tumor cell surface. Specific Aims and Study Design: Our microarray data showed that highly metastatic TM40D-MB cells had significant reduced level of CD1D1 expression than control TM40D cells (4.67 fold). The microarray data were confirmed in TM40D, TM40D-MB, and 4T1 (high metastatic) cells by RT-PCR and Western blot analyses. We, therefore hypothesize that reduced level of CD1D1 in breast tumor cells is one of the key requirements for their successful harboring in the bone environment. We have developed the following specific aims to test this hypothesis. Specific Aim 1: To determine the effect of overexpression of CD1D1 on breast tumor metastasis. Specific Aim 2: To determine the role of NKT cells in the prevention of breast cancer bone metastasis. Specific Aim 3: To understand how NKT cells recognize CD1D1-expressing tumor cells and the cytotoxic effect using cell culture system. Relevance: Bone metastasis is the most frequently found metastasis in breast cancer patients. Identifying bone metastasis specific genes and elucidating the mechanism of gene action may provide effective therapy for eradiating this malignant disease.

    Lay Abstract:
    LAY ABSTRACT Breast cancer is the most common cancer detected in women, accounting for nearly one out of every three cancers diagnosed in the United States. In 2004 alone, approximately 211,240 women were diagnosed with this disease. About 40,410 women died from this disease in that same year (American Cancer Society). Among breast cancer patients, the majority is associated with the bone metastasis. Such a high morbidity indicates that bone is a preferentially favored site for breast cancer metastasis. Bone metastasis is an extremely complicated process involving local invasion, intravasation and extravasation of vascular system, growth at bone marrow and angiogenesis. Many genes are involved in the control of these complicated processes. One unique aspect of tumor metastasis is that tumor cells use several smart choices to evade from immune surveillance and to co-exist with the host immune system. One immune response involves natural killer T (NKT) cell, a unique lineage of lymphoid in the organism, to fight against tumor cell growth and metastasis. NKT cells recognize CD1D-presented antigens and initiate the cytolysis of the antigen-presenting cells. Previous report showed that NKT cells were responsible for tumor rejection and prevention of experimental metastasis in liver, and we suspect that they might be involved in the tumor surveillance against bone metastasis. My laboratory has recently developed a syngeneic mouse model of breast cancer bone metastasis. Mouse mammary tumor TM40D-MB cells were implanted to mammary fat pad of Balb/c mice. Tumors developed in the mammary fat pads and became metastatic to the bone with an efficiency of 53%, mimicking the high rate (70%) of human breast cancer bone metastasis in patients. From this metastasis model, we isolated a sub-population of breast tumor cells with a high potential for bone metastasis. The gene expression profile of these cells has been compared with that of breast cancer cells with lower metastatic potential using Affymetrix microarray analysis. We identified CD1D1 as a candidate gene whose expression was significantly down-regulated in highly metastatic breast tumor TM40D-MB cells. We hypothesize that reduced level of CD1D1 in breast tumor cells is one of the key requirements for their successful harboring in the bone environment. We anticipate that in order for breast tumor cells to be able to escape from the immune surveillance and stay alive in bone environment with high amounts of NKT cells, they have to disrupt the CD1D1 mediated antigen presentation on tumor cell surface. In this proposal, we have developed several specific aims to study the role of CD1D1 in breast cancer bone metastasis. Identifying bone metastasis specific gene and elucidating the mechanism of gene action may provide effective therapy for eradiating this malignant disease.