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    Research Grants Awarded

    Role of IFIX in breast cancer metastasis

    Study Section:
    Tumor Cell Biology I

    Scientific Abstract:
    Breast cancer is the most commonly diagnosed cancer in the United States, accounting for one out of every three cancers. In the past, breast cancer research has been focused on tumor initiation and suppression of primary tumor growth. To data, the most effective treatment for breast cancer remains to be the surgical removal of the primary tumor. However, it is clear that most breast cancer patients do not die from primary tumor but from tumor metastasized to vital organs. Metastasis is an extremely complicated process. The mechanism underlying metastasis remains poorly understood. Drug design based on clear understanding the molecular players involved in breast cancer metastasis will certainly improve the survival of breast cancer patients. Our long-term goal is to identify essential molecules and to elucidate the signal pathways in breast cancer metastasis. We recently cloned IFIX, which is often down regulated in breast cancer. In contrast, the expression of IFIX is associated with growth inhibition, reduced transformation, and tumor regression in experimental systems. Thus, IFIX functions as a tumor suppressor. IFIX suppresses the invasiveness of breast cancer cells. Reduced invasiveness of IFIX-expressing breast cancer cells correlates with down regulation of HDAC1, which is known to be a major transcriptional repressor of extracellular matrix genes. In this proposal, our overall objective is to determine the role of IFIX in breast cancer metastasis. The central hypothesis is that IFIX is a metastasis inhibitory gene whose expression is lost during tumorigenesis. Due to down regulation of HDAC1 in IFIX-expressing breast cancer cells, HDAC1 may be a critical factor in IFIX-mediated suppression of breast cancer cell invasion. To test this hypothesis, we will determine (1) the role of IFIX in breast cancer metastasis models; (2) the role of HDAC1 in IFIX-induced suppression of invasiveness; and (3) the regulatory mechanism of HDAC1 by IFIX. The success of the proposed experiments will present IFIX as a novel drug target in metastatic breast cancer therapy.

    Lay Abstract:
    Metastatic breast cancer is one of the most deadly diseases among women in the United States. Although much research effort has concentrated on finding ways to prevent tumor initiation and primary tumor growth, the most effective treatment for breast cancer remains to be the surgical removal of the primary tumor. It is clear however that most breast cancer patients do not die from primary tumor but from tumor spread to other organs. Tumor spread or tumor metastasis is an extremely complicated process. How this process takes place remains poorly understood. Metastasis is an intensively investigated field in cancer research. Clear understanding of how metastasis occurs and the factors involved will certainly help to produce rationally designed drugs to combat invasive breast cancer cells and improve the survival of breast cancer patients. Our long-term goal is to identify molecules and signal pathways critically involved in breast cancer metastasis. We recently isolated IFIX, whose expression is often lost or reduced in breast tumor samples. In contrast, we observed a reverse of cancerous characteristic of breast cancer cells when we re-express IFIX in these cells. Therefore, IFIX is considered as a tumor suppressor. We also found IFIX could inhibit the ability of breast cancer cells to invade in experimental system. In addition, IFIX reduces the expression of an important cancer drug target, HDAC1, which is known to be a major repressor of genes involved in tumor invasion. In this proposal, our overall goal is to determine the role of IFIX in breast cancer metastasis. The central hypothesis is that IFIX is a metastasis inhibitory gene whose expression is lost during tumorigenesis. Since down regulation of HDAC1 in IFIX-expressing breast cancer cells, HDAC1 may be a critical factor in IFIX-mediated suppression of breast cancer cell invasion. To test this hypothesis, we will determine (1) the role of IFIX in breast cancer metastasis models; (2) the role of HDAC1 in IFIX-induced suppression of invasiveness; and (3) the regulatory mechanism of HDAC1 by IFIX. The success of the proposed experiments will present IFIX as a novel drug target in metastatic breast cancer therapy.