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    Research Grants Awarded

    Role of Telomere Dysfunction and Telomerase Reactivation in Breast Carcinogenesis

    Study Section:
    Postdoctoral Fellowship

    Scientific Abstract:
    The benign-to-malignant transition in human breast cancer is associated with an increase in chromosomal aberrations. These genomic alterations, including amplifications and deletions, presumably target oncogene and tumor suppressor gene loci integral to the malignant process. Previous studies in the telomerase knockout mouse demonstrated that telomere dysfunction, along with deactivated DNA damage checkpoints (e.g. p53 mutation), can fuel rampant genomic instability and promote the development of epithelial cancers. Whereas telomere dysfunction serves to drive cancer initiation, it is now believed that full malignant progression requires the activation of telomere maintenance mechanisms— achieved typically by activation of telomerase. Here, I seek to secure genetic evidence that will validate the telomere hypothesis of breast carcinogenesis by modeling and assessing the relative impact of telomere dysfunction, p53 mutation and telomerase reactivation in the breast epithelium and neoplasms of mice. Specifically, I will utilize this model system to investigate several aspects of the disease including: (1) the role of telomere-based chromosomal instability and compromised telomere checkpoints in the initiation of breast oncogenesis, (2) the impact of somatic telomerase reconstitution on the transformation of breast epithelium and on the progression of initiated breast neoplasms, and (3) the role of telomere dysfunction in producing the high degree of genomic complexity and specific amplifications and deletions observed in the human disease. Telomerase will be reactivated in normal or neoplastic tissue of late generation telomerase/p53 deficient mice by infection of breast epithelial cells with telomerase-carrying lentivirus or alternatively, by tamoxifen treatment of mice with an inducible ER-TERT allele. The latency, penetrance, histopathology, metastatic potential, and genomic profile of the arising tumors will be examined. If our modeling efforts prove successful, we will not only gain an understanding of the role of telomeres and genomic instability in a major human cancer but also create a model that may serve as a platform for comparative oncogenomics and cancer gene discovery. In the long run, one can anticipate that such a model with human-like genomic instability may generate a more appropriate preclinical model with which to conduct preclinical testing of novel chemotherapeutic and chemopreventive agents.

    Lay Abstract:
    The benign-to-malignant transition in human breast cancer is associated with an increase in chromosomal changes. It is believed that this is caused, at least in part, by the shortening of telomeres, the structures that protect the ends of chromosomes. The gradual erosion of telomeres is part of the natural aging process, and it may drive chromosomal instability. As a result, aspiring cancer cells can accumulate the multiple genetic aberrations needed to become malignant. However, this ongoing instability has to be quenched to ensure viability and achieve a fully malignant state. This is accomplished in ~90% of breast tumors by activating telomerase, a complex that lengthens telomeres. Still, the actual mechanism by which telomerase facilitates tumorigenesis in vivo, and the stage at which its activation is required, are not known. We propose to use a mouse model to investigate these issues. Unlike most animal models of breast cancer (which have long telomeres and widespread telomerase activity), our mouse model has no telomerase (knockout) and harbors short, dysfunctional telomeres. Moreover, our mice lack a copy of p53, the “guardian” of chromosomes, making them prone to higher levels of instability (similar to that seen in human pre-cancerous lesions). Our specific aims are: (1) to study the role of chromosomal instability in the initiation of breast cancer in vivo, (2) to establish whether telomerase activation is required for tumor initiation, maintenance, or both, and (3) to study what chromosomal aberrations are important to the malignant process. We have devised alternative methods to activate telomerase in the mouse breast, either by introducing a virus carrying the telomerase gene, or by using a variant of the knockout model, in which the telomerase complex can be induced with a drug. We will score the appearance of tumors, their penetrance, latency, rate of growth, metastatic potential, etc. We will also assess their level of genomic complexity, and study those chromosomal aberrations that are also found in human breast cancer patients. We believe that our studies will provide a more articulate understanding of telomere-based instability and telomerase activation, a nearly universal step in tumor development. A number of telomerase inhibitors have been developed in the last few years, and our findings may facilitate and speed up their application at the clinical level.