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    Significance of Histone Deacetylase Inhibitors in Breast Cancer

    Scientific Abstract:
    TECHNICAL ABSTRACT Significance of Histone Deacetylase Inhibitors in Breast Cancer Background: Current therapeutic approaches to treat breast cancer are associated with toxic side effects because these drugs do not discriminate between normal and tumor cells. Therefore, new drug development approaches should aim at developing drugs that specifically kills tumor cells without affecting normal cells. Histone deacetylase (HDAC) inhibitors and TRAIL (TNF-related Apoptosis Inducing Ligand) specifically induce apoptosis in tumor cells with no effect on normal cells, and both are at the early stages of clinical development. We have recently noticed that most breast cancer cell lines are resistant to TRAIL, and TRAIL-resistant cancer cell lines can be sensitized by HDAC inhibitors. The mechanisms by which HDAC inhibitors induce sensitivity in TRAIL-resistant breast cancer cells are not known. Therefore, understanding the molecular mechanisms of inducing sensitivity by HDAC inhibitors are important issues for effective breast cancer therapy. Objectives/Hypothesis: The objectives of this proposal are to understand the intracellular mechanisms by which HDAC inhibitors and TRAIL can be combined to kill specifically cancer cells in vitro and in vivo. We hypothesize that HDAC inhibitors sensitize breast cancer cells to undergo apoptosis by TRAIL through up-regulation of death receptors DR4 and/or DR5, and activation of caspase(s). Specific Aims: The specific aims of this project are 1): To determine the intracellular mechanisms by which HDAC inhibitors sensitize TRAIL-resistant human breast cancer cells; and 2) To validate whether combination treatments of histone deacetylase inhibitors and TRAIL induce apoptosis, and inhibit tumor growth in a human breast cancer xenograft model. Study Designs: The intracellular mechanisms by which HDAC inhibitors sensitize breast cancer cells to TRAIL will be investigated by measuring cell viability, apoptosis and gene expression. The combinations of HDAC inhibitors and TRAIL will be validated in a human-mouse xenograft model system. Potential Outcomes and Benefits of the Research: The basic knowledge obtained from these studies will lead to the development of potent and non-toxic anticancer therapeutic agents for subsequent use in clinical trials. The combination of HDAC inhibitors with TRAIL will allow us to develop a less toxic and more effective therapeutic approach for the treatment of breast cancer even if they progress to estrogen-independent.

    Lay Abstract:
    Significance of Histone Deacetylase Inhibitors in Breast Cancer Breast cancer is the second leading cause of cancer related deaths in women in United States, after lung cancer. The recurrence of breast cancer is largely due to progression of initially estrogen-dependent breast cancer cells to tumor cells that do not depend on estrogen for their proliferation. The reason for this loss of estrogen dependency is not known. Therefore, the developments of new agents that kill both estrogen-sensitive and -insensitive cancer cells are required for effective breast cancer therapy. One such approach is the activation of death receptor pathway by the ligand TRAIL (TNF-related Apoptosis Inducing Ligand). The activation of cell surface death receptors by TRAIL induces apoptosis (programmed cell death) in both estrogen receptor-positive and -negative breast cancer cells, but has no affect in normal cells. TRAIL kills primarily cancer and transformed cells without appreciable affect on normal cells. Unfortunately, unlike other cancers, a majority of breast cancer cell lines are resistant to TRAIL. The precise mechanisms of the TRAIL resistance are unknown. Our preliminary data have shown that TRAIL-resistant breast cancer cells can be sensitized with histone deacetylase (HDAC) inhibitors. Since TRAIL and HDAC inhibitors kill primarily cancer cells with no effect on normal human cells, and are at early stages of clinical development, combining these drugs for the treatment of breast cancer will be a novel approach. We hypothesize that HDAC inhibitors sensitize breast cancer cells to undergo apoptosis by TRAIL through up-regulation death receptors and activation of caspase(s). We will investigate the intracellular mechanisms by which HDAC inhibitors sensitize breast cancer cells to TRAIL. Then, we will use an animal model system to determine if this effect of sensitizing tumor cells by HDAC inhibitor to TRAIL-induced killing also works in tumors growing in nude mice. This research project is a novel approach to make cells more sensitive to treatment based on understanding the specific abnormalities occurring in the cancer cells and is potentially applicable to clinical use. Furthermore, the use of HDAC inhibitor and TRAIL will have additional clinical advantage because the activation of death receptor pathway will kill mainly breast cancer cells even if they progress to estrogen-independent.