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    Research Grants Awarded

    Detection and Analysis of Telomere Dysfunction in Breast Tumor Tissue

    Study Section:
    Tumor Cell Biology V

    Scientific Abstract:
    Background: Loss of telomere function is known to result in telomere fusions causing genomic instability via breakage-fusion-bridge cycles during subsequent cell cycles. The goal of this proposal is to establish the extent of telomere dysfunction during breast tumorigenesis. Several recent reports support this hypothesis, yet the extent of telomere dysfunction in human breast cancer has not been directly determined. The research proposed here is innovative because we have developed a method to directly detect and analyze telomere dysfunction from tumor tissue. Using this innovation, we have generated critical preliminary evidence that: 1) breast tumors, but not normal tissue, contain telomere fusions; and 2) telomere fusion junctions contain relatively short fragments of non-telomeric, previously identified fragile DNA regions. Objective/Hypothesis: The objective of this application is to directly determine the extent of telomere dysfunction during breast tumorigenesis. The central hypothesis of this proposal is that telomere dysfunction is one of the key driving forces behind the genomic instability observed in early breast lesions. We propose that telomere capping is disrupted in a small subset of normal breast epithelial cells. This loss of telomere function then results in telomere fusions via recombinational mechanisms, causing genomic instability via breakage-fusion-bridge cycles during subsequent cell cycles. Specific Aim: Here we directly test the hypothesis that telomere dysfunction is an important cause of genomic instability in breast cancer by the following specific aim: 1) determine the extent of telomere fusions in breast tumor tissue. Study Design: We will use our recently developed method to detect and analyze telomere fusions from isolated genomic DNA. Our preliminary results indicate that telomere fusion junctions contain relatively short fragments of non-telomeric, previously identified fragile DNA regions within the telomere-to-telomere fusion junctions. This finding provides us with critical clues regarding possible mechanisms responsible for the formation of these fusion junctions, which are likely formed via recombinational modes. Additionally, using our telomere fusion detection method, we have found three specific classes of fusion junctions that occur both in a human mammary epithelial model system and breast tumor tissue. We will test the stage during tumorigenesis in which fusions occur and the prevalence of telomere dysfunction in multiple breast tumor samples to determine the prognostic significance of these findings. In addition, we will determine whether only specific or any chromosome can form telomere fusions in tumor tissue samples. Potential Outcomes and Benefits of the Research: These studies will be critical for further understanding of the cause and extent of telomere dysfunction in breast cancer. Notably, from our preliminary results, we expect the occurrence of telomere dysfunction to be an early event in the development of breast cancer. Therefore, translational applications for early detection and treatment are expected to be highly relevant.

    Lay Abstract:
    Background: One of the earliest changes known to occur in the development of breast cancers is that the DNA genome is disturbed or rearranged within a small subset of normal breast cells. This rearrangement of the genome has very negative effects, causing normal cell growth to become uncontrolled. Cells that lose growth control then divide abnormally, potentially developing into a cancerous tumor. Recently, there has been an accumulation of evidence that the proper maintenance of the very ends of chromosomes (telomeres) might play an important role in loss of genome integrity observed during breast cancer development. The enzyme responsible for synthesizing the specific DNA at the ends of chromosomes, telomerase, is activated in almost all breast tumors that have been examined in this way. In addition, mice, which normally do not develop breast cancer, develop breast adenocarcinomas by the artificial creation of a dysfunctional or non-capped telomere. Objective/Hypothesis: Our objective is to determine how breast cancer starts. Since loss of genome stability occurs very early, we are interested in determining what exactly is responsible for these adverse genomic rearrangements. Specifically, we are testing whether loss of telomere capping takes place during breast cancer development. Our hypothesis is that the ends of chromosomes become uncapped or unprotected and then fuse or recombine with other uncapped telomeres or broken chromosome ends. Once chromosomes fuse together, chromosomes will break or the number of chromosomes will be disturbed in the daughter cells produced during subsequent cell divisions. Therefore, genomic instability ultimately leads to the development of breast cancer. Specific Aims: Here we directly test the hypothesis that telomere dysfunction is an important cause of genomic instability in breast cancer by determining the extent of telomere fusions in breast tumor tissue. Study Design: We have developed an innovative method to detect and analyze telomere fusions from isolated genomic DNA initially using cell lines with known percentages of telomere fusions. Importantly, we discovered recently that telomere fusion junctions contain relatively short fragments of previously identified fragile DNA sites within the telomere-to-telomere fusion junctions likely resulting from multiple breakage-fusion-bridge cycles. Finding these DNA sequences at the fusion junctions now gives us important clues into the ways these junctions are likely formed. Additionally, using our telomere fusion detection method, we have found that telomere fusions are present in breast tumor tissue. Therefore, we can now test whether telomere fusions occur early in tumorigenesis and the prevalence of telomere dysfunction in multiple breast tumor tissue samples. Potential Outcomes and Benefits of the Research: Notably, from our preliminary results, we expect the occurrence of telomere dysfunction to be an early event in the development of breast cancer. Therefore, translational applications for early detection and treatment are especially relevant. Finding this molecular marker (telomere fusion junction) for early breast tumorigenesis may give us a key for detecting early forms of breast cancer and is expected to be useful for prevention and treatment strategies.