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    Research Grants Awarded

    Mechanisms Of Telomere Dysfunction In Breast Cancer

    Grant Mechanism:
    Career Catalyst Research

    Scientific Abstract:
    1) Scientific rationale Telomere dysfunction is likely a key driving force behind the genomic instability observed in early cancer lesions. Since genomic instability is one of the earliest neoplastic changes known to occur in tumorigenesis, determining its cause(s) is critical for understanding the etiology of cancer for early detection and therapeutic purposes. Several recent reports support the concept that defects in telomere maintenance initiate genomic instability eventually resulting in the development of breast cancer and other cancers. However, the extent of telomere dysfunction in human cancers has not been directly determined due to technical limitations in detecting telomere dysfunction within tissues. This application focuses on an innovative PCR-based method for detecting telomere dysfunction markers in breast tumor tissue and corresponding circulating DNA for early breast cancer detection. (2) Hypothesis Our working hypothesis is that telomere dysfunction is a key cause of genomic instability observed in breast cancer. To test this hypothesis, we will determine whether telomere dysfunction is found in human breast tumor tissue and corresponding circulating DNA. (3) Research aims and design: Detection of telomere dysfunction in tumor tissue and circulating DNA from breast cancer patients. Our preliminary results indicate that telomere dysfunction does indeed occur with high frequency in human breast tumor tissue using our innovative PCR-based method. Moreover, telomere fusion junctions contain insertions of relatively short regions of non-telomeric DNA derived from known highly recombinagenic regions such as fragile sites and subtelomeric regions witin the telomere-to-telomere fusion junctionss likely formed via recombinational mechanisms resulting in multiple breakage-fusion-bridge cycles. The experiments in this proposal are designed to develop these telomere dysfunction and genomic instability markers for early detection of breast cancer. We will perform pilot studies to determine the extent of telomere dysfunction, as measured by telomere fusion accumulation, in multiple staged tumor tissue samples and corresponding circulating DNA. (4) Clinical impact In this proposal, we will determine the tumorigenesis stage when chromosome fusions occur and the prevalence of telomere dysfunction in multiple staged breast tumor tissue samples and corresponding circulating DNA. Based upon our preliminary results, we anticipate that we will be able to develop a simple, accessible clinical test for very early detection of breast cancer. By using our innovative PCR-based method to identify these molecular markers (chromosome fusion junctions) in the early stages of breast tumorigenesis, we may be able to provide an immensely useful diagnostic tool for detection, prevention, and treatment of breast cancer.

    Lay Abstract:
    Chromosomes are the parts of a cell that contain genes, which determine hereditary traits. Telomeres are specialized structures at the end of chromosomes that are essential for chromosome maintenance. Telomeres have been shown to be important for protecting the chromosomes from degradation and chromosome end fusion with another separate chromosome. Therefore, disruption of telomere function (called ?telomere dysfunction?) causes havoc to cell survival. This in turn compromises not only cellular lifespan, but also the susceptibility of the organism to age-related diseases such as cancer. Telomere dysfunction is likely a key driving force behind the genomic instability (also called as ?chromosomal instability?) observed in early cancer lesions. Since genomic instability is one of the earliest neoplastic changes known to occur in tumorigenesis, determining its cause(s) is critical for understanding the etiology of cancer for early detection and therapeutic purposes. Several recent reports support the concept that defects in telomere maintenance initiate genomic instability eventually resulting in the development of breast cancer and other cancers. Since early detection is clearly the best defense against cancer, this application focuses on an innovative technique for detecting telomere dysfunction markers in breast tumor tissue and corresponding circulating DNA for early breast cancer detection. We have developed a unique and powerful technique to detect and analyze chromosomal end-to-end fusions (a major hallmark of telomere dysfunction).. Based upon our preliminary results, we anticipate that we will be able to develop a simple, sensitive and accessible clinical test for very early detection of breast cancer. By using our technique to identify these molecular markers (chromosome fusion junctions) in the early stages of breast tumorigenesis, we may be able to provide an immensely useful diagnostic tool for detection, prevention, and treatment of breast cancer.