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    Research Grants Awarded

    Mechanisms Of Metal Binding Compounds-Induced Cyclin D1 Mrna Degradation In Breast Cancer Cells: The Involvement Of Microrna And RNA Processing Bodies

    Grant Mechanism:
    Investigator Initiated Research

    Scientific Abstract:
    Metal binding compounds have been increasingly recognized as anticancer agents, but the mechanisms of their action remain poorly understood. Processing bodies (P-bodies) are RNA granules that are highly enriched in discrete and prominent foci within the cytoplasm of mammalian cells. The newly identified P-bodies are involved in important posttranscriptional events, such as small RNA interference, regulation of protein translation, and microRNA-mediated mRNA degradation. We have observed that clioquinol, a metal ionophore, enhances P-body formation and destabilizes cyclin D1 mRNA in breast cancer cells. Based on previous reports and advances in modern cell biology, we hypothesize that clioquinol?s anticancer activity is associated with P-body-mediated mRNA degradation in breast cancer cells. We propose two specific aims to test this hypothesis. Specific Aim 1: to characterize clioquinol-induced alterations of P-bodies in breast cancer cells. This effort is intended to establish the effects of clioquinol on the assembly of P-bodies in breast cancer cells. We will first characterize the effects of clioquinol on the expression of various cellular molecules that are associated with P-bodies using human breast cancer cell model systems. The importance of metals such as zinc and copper in clioquinol-induced assembly of P-bodies will be addressed. Specific Aim 2: to examine the potential involvement of microRNAs in P-body-mediated cyclin D1 mRNA degradation. MicroRNAs are known to target mRNAs to P-bodies for degradation. In this section, we will determine whether the degradation of cyclin D1 mRNA is associated with some of the microRNAs identified through bioinformatics. The findings from breast cancer cell lines will be verified using breast cancer xenografts grown in nude mice. We anticipate that completion of this study will have significant impact in several areas of breast cancer research, including identification of novel therapeutic targets, development of new anticancer agents, and advancement of our knowledge of the basic biology of breast cancer cells.

    Lay Abstract:
    The objective of this study is to understand the contributions of cellular granules (P-bodies) and microRNAs in clioquinol (a metal binding compound)-induced stability changes of an important mRNA species, cyclin D1, in breast cancer cells. Cyclin D1 is a key regulator of cell cycling, and has been suggested as one of the molecular targets for cancer therapy. Understanding how this molecule is being regulated and targeted in cancer cells will provide critical information for the development of novel anticancer agents. Many cellular factors may mediate cyclin D1 gene expression. Among them, the newly recognized P-bodies and microRNAs are the most likely mediators of cyclin D1 mRNA stability. It is established that P-bodies are cytoplasmic complexes where mRNA degradation takes place, and that microRNAs target mRNA degradation of P-bodies in mammalian cells. Our preliminary studies show that clioquinol enhances the assembly of P-bodies in breast cancer cells and that several microRNAs may bind to the cyclin D1 mRNA and regulate its stability. We hypothesize that clioquinol?s anticancer activity is associated with P-body-mediated mRNA degradation in breast cancer cells. We propose two specific aims to test this hypothesis: 1. to characterize clioquinol-induced alterations of P-bodies in breast cancer cells. 2. to examine the potential involvement of microRNAs in P-body-mediated cyclin D1 mRNA degradation. We anticipate that completion of the proposed studies will not only advance our knowledge in breast cancer biology, such as the regulation of cyclin D1 expression by microRNAs and P-bodies, but may also identify novel molecular targets for breast cancer therapy, such as microRNA species and P-bodies. Since clioquinol has been used in humans for many years, the proposed mechanistic studies will provide the basis for further development of this compound into clinical practice for breast cancer treatment.