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Role of Telomerase and Telomeres in the Tumorigenesis of Breast Cancer
Background: Telomerase and telomere maintenance are associated with the development, progression, and metastasis of malignant tumors: (i) telomerase activity is present in approximately 90% of human malignant tumors; (ii) enforced expression of mTERT results in increased development of breast cancer; (iii) inhibition of telomerase limits the life-span of human cancer cells and results in their death. However, there is much we still do not know about the telomerase biology and its mechanistic basis in tumorigenesis, especially in tumorigenesis of breast cancer. Objective/Hypothesis: The proposal will generate and characterize telomerase-null mice transgenic for PyMT oncogene and MUC1 tumor-associated antigen (mTERC–/–MMT) for six generations. The second objective is to determine the role of telomerase and telomere maintenance in the development of breast cancer. Our hypothesis is that telomerase is an essential component of neoplastic transformation, growth and metastasis in spontaneous mammary carcinomas. Specific aims: (i) To breed, select, and characterize mTERC–/–MMT mice lacking telomerase activity for six generations. (ii) To determine in mTERC+/+MMT and mTERC–/–MMT mice the temporal sequence of telomerase activation, telomere shortening, malignant transformation, and metastasis. Study Design: MMT and mTERC+/– mice will be crossed to obtain mTERC heterozygotes transgenic for PyMT oncogene and MUC1 antigen (mTERC+/–MMT). These mice will be mated with mTERC+/– mice to produce the first generation (G1) of mTERC–/–MMT. The G1 mice will be mated to produce the second generation of mTERC–/–MMT mice. This mating scheme will continue until the sixth generation of mTERC–/–MMT mice (G6). Female mTERC–/–MMT mice from G1 to G6 and their littermate controls will be used to characterize the tumorigenesis and metastasis of breast cancer. In Specific Aim 2, we will perform a detailed analysis of the temporal sequence of telomerase activation, telomere shortening, tumorigenesis, and metastasis in mTERC+/+MMT and mTERC–/–MMT mice to determine the role of telomerase and telomere maintenance in tumor initiation, progression, and metastasis. Potential Outcomes and Benefits of the Research: The proposed study will directly address an important issue in the tumorigenesis of breast cancer whether telomerase activity is an essential component of neoplastic transformation, growth, and metastasis, and, if so, whether such tumorigenesis is mediated by telomere maintenance. We expect that telomerase is required for full malignant transformation, growth and metastasis of breast cancer.
Telomeres, a vital part of the cell, are structures that cap the end of chromosomes. They are the biologic clock that controls cell division. All cells begin with a fixed telomere length which varies among species and cell types. Due to the inability of cells to replicate the extreme ends of their chromosomes, the telomere will shorten with every cell division. When a cell’s telomere shortens to what is known as a critical point, a cell will either stop dividing or lapse into cellular senescence. If cells are transfected with an cancer-causing gene (oncogene), they can overcome senescence and continue to divide until cellular crisis occurs. Most cells that enter crisis will die, but some cells will emerge from crisis and become cancerous. One unique characteristic for these cells is that they are positive for telomerase activity. Telomerase is composed of an RNA subunit that acts as an RNA template and a reverse transcriptase catalytic subunit that functions to maintain the telomere length. It has been recognized that the telomerase plays a critical role in the tumor formation and growth through mechanisms such as the control of cell division by maintaining the length of telomeres. Indeed, telomerase is active in approximately 90% human malignant tumors. However, most of the telomerase-related studies were done in the cultured cells. Furthermore, little information is available about the role of telomerase and telomere maintenance played in the breast cancer formation and progression due largely to the lack of a proper animal model. In the proposal, we will generate mice with deficient telomerase, and therefore unable to maintain telomere length but express an oncogene called PyMT that will cause spontaneous breast cancer formation by breeding mTERC-deficient mice (no telomerase activity) with MMT mice (mice express PyMT oncogene and develop spontaneous breast cancer). This mouse model will provide a powerful tool to determine: i) whether telomerase is required for the breast cancer formation; ii) whether telomere maintenance is required for the breast cancer formation; iii) if yes, what is their mechanism? More important, the mice in the late generations (generations 4 or 5) shows significant telomere shortening due to lack of telomerase activity. Taken together, the proposed study addresses an important issue in the breast cancer development and the proposal is novel since no such study has been reported. In addition, the proposed work will be performed in a model closely mimics breast cancer in humans, and thus is highly relevant to the breast cancer research.