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    Research Grants Awarded

    Telomerase recruitment as a novel target in breast cancer treatment

    Study Section:
    Postdoctoral Fellowship

    Scientific Abstract:
    Background Telomeres consist of repetitive DNA sequences and their associated binding proteins that "cap" the chromosome ends, preventing them from being recognized as broken DNA. Normal cells loose telomeric sequences with each cell division, a process that eventually induces senescence. For long term proliferating cells, such as cancer cells, it is essential to counteract telomere shortening by telomerase reactivation to prevent a growth arrest. Because of the tumor specific expression of telomerase, it has emerged as a promising cancer therapeutic target. Recently there has been tremendous progress in the understanding of telomerase biogenesis and enzymology. Despite this progress, it remains unclear how telomerase, a low abundant enzyme, is recruited to chromosome ends. Objective/Hypothesis The overall objective of this proposal is to investigate the mechanism by which telomerase is recruited to the telomeres and identify the factors mediating its recruitment. A thorough analysis will be done to determine the role of telomerase "recruiter" (s) in promoting cell immortality during tumorignesis. By inhibiting the function of the recruiter, we aim to increase the rate of telomere shortening of breast cancer cells, thereby dramatically reducing their lifespan. Specific aims 1) Develop an assay to screen for the telomerase-recruiter. 2) Screen for candidate recruiters in an shRNA library. 3) Characterize the telomerase-recruiter(s) through functional studies. Study Design An assay system will be developed to allow the screening for the recruiter. The assay is based on creating a cell system from MEFs (mouse embryinic fibroblast) that expressess a mutated from of telomerase RNA. In this setting, telomerase activity will be toxic to the cells, and can only be reverted by blocking telomerase access or recruitment to the end. Once the system is validated, it will be used to screen a genome wide ShRNA library using high throughput technlogy. This screen is predicted to yeild mutliple hits which will be validated by a series of tests to identify the one that affects telomerase recruitement. Once the recruiter is identified, I will characterize its function and assess its role in tumor cell immortalization. Potential Outcomes and Benefits of research We are at a point where telomerase inhibitors are about to enter clinical trials, and the most challenging part of telomerase biology lies in the mechanism that recruits it to where it needs to function. Regulation of telomerase access to telomeres is a key step for cancer cells to guarantee their indefinite proliferative potential. Uncovering the mechanisms underlying this process will lead to the understanding of the main step leading to cancer cells immortality. The identification of specific molecules involved in this regulatory pathway could unveil potential targets to reverse the indefinite proliferation capacity of cancer cell.

    Lay Abstract:
    Normal human cells lose DNA from the end of their chromosomes (the telomeres) after every replication cycle until they quit dividing and undergo growth arrest. Cells that divide indefinitely, such as cancer cells must activate telomerase, an enzyme that adds repeats to the chromosomal end, to circumvent telomere loss. Studies have shown that while normal somatic cells lack telomerase activity, 14% of benign breast tumors, 92% of breast carcinomas in situ, and 95 % of invasive breast cancers show a marked increase in telomerase activity, making it a hallmark of tumor progression. Being an obligate means for the indefenite growth of cancer cells, telomerase constitutes a very promising target for cancer therapy. Understanding the details of its action is a key issue to allow telomerase to be further explored in cancer therapy. While much is known about the enzyme, its regulation and its mode of action, there is no information on how it is recruited to the telomeres. I plan to decipher the mechanism of telomerase recruitment and understand its role in tumor progression. I will develop an assay that will allow me to screen for genes that are involved in telomerase reruitment. Once the assay is validated, I will peform a genome-wide screen using an shRNA library. The final step will be to study the function of the identified gene(s) in promoting tumor cell proliferation and determine the effect of inhibiting those gene (s) on breast cancer cell survival. Breast cancer is the most common cancer in women worldwide, and after lung cancer, it is the second most fatal cancer in women. One out of 12 women who reach the age of 90 in the western world is likely to develop breast cancer. Current breast cancer therapies include treatments that are cytotoxic and susceptible to drug resistance. Since telomerase is absent from normal cells and is activated in tumor cells, targeting factors responsible for telomerase recruitment constitute promising breast cancer therapeutic targets with minimal side effects.