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Mechanisms Of IRF-1 Induced Apoptosis In Breast Cancer
Tumor Cell Biology III
IRF-1 is a nuclear transcription factor that is not only induced by interferons, but also other cytokines, retinoids, and even anti-estrogens in breast cancer. IRF-1 is proving to be a major mediator of apoptosis for several novel and established agents against breast cancer. We have shown that overexpression of IRF-1 in breast cancer cells results in marked apoptosis and suppression of tumor in vitro and in vivo in both mouse and human breast cancer, while sparing non-malignant breast cells. We have preliminary data demonstrating IRF-1 involvement in both the death receptor pathway, and mitochondrial pathway of apoptosis. Our objective is to further elucidate the mechanism of IRF-1 induced breast cancer specific apoptosis. We hypothesize that IRF-1 promotes pro-apoptotic interactions with components of both extrinsic and intrinsic death pathways in breast cancer cells but not non-malignant breast cells. Our Specific Aims are: I) Determine differences in IRF-1 induced apoptotic and anti-apoptotic signaling in breast cancer cells versus non-malignant breast cells, II) Determine the role of mitochondrial IRF-1 in apoptosis of breast cancer cells versus non-malignant breast cells and III) Evaluate the mechanism of IRF-1 induced apoptosis in vivo and enhance apoptosis by a combinatorial approach in a mouse model. In Aim I, we hypothesize that IRF-1 induced apoptosis is FADD-dependent and that different proteins interact with FADD in breast cancer cells versus non-malignant breast cells, and that NF-kB activation plays a role in breast cancer specific apoptosis. In Aim II, we hypothesize that mitochondrial IRF-1 plays a role in apoptosis of breast cancer cells versus non-malignant cells. We will assess the location and sub-localization of IRF-1 in mitochondria in cancerous and non-cancerous cells. Based on sub-localization we will assess the interaction of IRF-1 with known mitochondrial apoptotic related proteins or with mitochondrial DNA. In Aim III, we hypothesize that the combination of Ad-IRF-1 with adriamycin will result in enhanced antitumor effects in vivo. We will perform immunohistochemistry to further elucidate the mechanism of IRF-1 induced apoptosis of breast cancer cells in vivo. Further understanding of the mechanism of IRF-1 induced apoptosis in breast cancer will allow us to find ways to enhance the efficacy of not only direct IRF-1 treatment but also agents that cause apoptosis through IRF-1.
IRF-1 is a protein inside cells that up-regulates genes involved in fighting viruses and other foreign intrusions to cells, including cancer. Several new and established agents against breast cancer, including tamoxifen and faslodex, are known to cause apoptosis, or programmed cell death in breast cancer cells; IRF-1 has been found to be responsible for these apoptotic effects. We have shown that IRF-1 can cause marked apoptosis and suppression of breast cancer cell lines in cell culture and in mouse models, yet non-malignant breast cells appear spared. Our objective is to further understand how IRF-1 causes breast-cancer specific apoptosis. We postulate that IRF-1 acts on different pathways inside the breast cancer cells that causes them to kill themselves. One goal is to evaluate how IRF-1 interacts with a protein called FADD, which is well known to play an essential role in causing death in cancers that are treated with apoptotic agents. We can precipitate FADD and look at proteins that are bound in the precipitate to see if there are differences in protein interactions in cancerous and non-cancerous cells. Another goal is to determine the role of mitochondria in the apoptosis caused by IRF-1. Mitochondria, which are found in all cells and are normally involved in providing energy to cells, have been known to play a very important, frequently alternate, role in apoptosis. We have found that IRF-1 seems to not only go to the nucleus where it activates genes, but also seems to go to these mitochondria outside of the nucleus. We will determine the exact location of IRF-1 in the mitochondria to determine how IRF-1 might act to promote apoptosis via the mitochondria. Our last goal is to see if direct IRF-1 treatment along with the established chemotherapeutic, adriamycin, can cause more apoptosis and tumor suppression together than with either agent alone in a mouse model of breast cancer. We will look at treated tumors under the microscope to try to further understand how IRF-1 causes apoptosis in mice. We feel that understanding how IRF-1 causes apoptosis in breast cancer can allow us to find ways to improve not only direct treatments with IRF-1 but also the new and established treatments that cause apoptosis through IRF-1.