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    Understanding Telomere Dynamics in Breast Cancer

    Scientific Abstract:
    Understanding Telomere Dynamics in Breast Cancer Scientific abstract: Background: The vast majority of human cancers including breast cancer are characterized by the presence of genomic instability. Although genomic instability comes in different forms, chromosomal instability appears to dominate carcinoma development and is an important characteristic of human breast cancer. Recent studies suggest that telomere dysfunction can drive the type of chromosomal instability seen in sporadic human breast cancer. Telomeres are nucleoprotein structures that cap the physical termini of all eukaryotic chromosomes and help in maintaining the integrity of the genome. The synthesis and maintenance of telomeres is mediated by a ribonucleoprotein complex called telomerase that includes an RNA template (Terc) and a reverse transcriptase catalytic subunit (Tert). A majority of normal human somatic cells lack detectable telomerase activity and exhibit progressive telomere shortening whereas 90% of human cancers including mammary cancers have reactivated telomerase and maintain telomeres at a much shorter but stable length. Conventional mouse models of breast cancer involving constitutive activation of oncogenes or inactivation of tumor suppressors have been very useful in understanding the genes and pathways involved in tumorigenesis but they do not reproduce the chromosomal instability and stochastic genetic changes usually seen in human breast cancers. We are developing a novel mouse model that closely mimics important aspects of human breast cancer development including telomere shortening, telomerase reactivation and stochastic genetic alterations driven by severe chromosomal instability. Objective/Hypothesis: The objective of this proposal is to create a mouse model of breast cancer that accurately recapitulates the telomere dynamics of human breast cancer. Studies with telomerase deficient mice have shown that telomere dysfunction and loss of the p53 checkpoint promotes formation of epithelial cancers including breast cancer. Although this model allows for potent initiation, tumor progression was significantly impaired and never metastasized. Our working hypothesis is that critical telomere shortening that accompanies organ renewal brings about chromosomal instability and initiates tumor formation. However, persistent telomere dysfunction in these cancers blocks efficient progression to invasive and metastatic stages unless telomerase is reactivated and brings about chromosomal stability. Specific aims: 1.To study the role of telomere dysfunction in breast cancer initiation in a tissue-specific way in the mammary gland. 2. To determine the role of telomerase reactivation in promoting breast cancer progression. 3. To study the effects of telomere dysfunction on proliferation and survival of mammary epithelium during the different stages of mammary gland development. Study design: The methods that will be utilized include generation and characterization of mice having novel conditional alleles of the telomerase catalytic subunit, Tert and p53 that can be inactivated in a mammary specific fashion. These mice will be engineered to reactivate telomerase in a spatially and temporally regulated fashion in the mammary gland. We will incorporate mammary specific expression of luciferase that will allow us to perform in vivo imaging to track tumor metastases. In addition to histological analysis of tumors, we will study the chromosome structure by spectral karyotyping (SKY). Potential outcomes and benefits: The studies proposed here will help us better understand the molecular events that occur during breast cancer progression and facilitate early detection. Understanding the role of telomerase in human breast cancer progression can be useful in the development of preventive and therapeutic strategies.

    Lay Abstract:
    Understanding Telomere Dynamics in Breast Cancer Lay abstract: Background: Exciting progress has been made in the last few years in our understanding of the genes and pathways involved in breast cancer. Despite these achievements, our understanding of the molecular events underlying breast carcinoma remain incomplete and has thwarted the efforts to develop rational therapies for treating breast cancer. Mouse models of human diseases such as breast cancer have enormous potential in contributing to our understanding of the genetic and molecular basis behind the diseases and will help us in developing novel strategies for clinical treatment. The vast majority of human breast cancers are characterized by the presence of unstable chromosomes. Existing mouse models of human breast cancer do not accurately mimic this very important characteristic of breast cancer. We are proposing to build a novel mouse model that will accurately represent the chromosomal instability that occurs in human breast cancer. One of the ways chromosomes break down is when the sequences they have at their ends called telomeres becomes very short. Telomeres are DNA sequences present on the ends of all our chromosomes and protect them from breaking down and joining with other chromosomes. Telomeres are made by a special enzyme called telomerase. Most human cells do not express telomerase and our telomeres shorten as we age and limit the ability of our cells to proliferate. Cancer cells learn to reactivate telomerase and this allows them to proliferate indefinitely and become immortal. Objective/Hypothesis: Our hypothesis is that breast cancer is caused by a two step process, both of which involve telomeres. The first step involves shortening of our telomeres and chromosomal breakdown as we age. Our body tries to protect itself by activating a gene called p53, which plays the role of caretaker of our genome and helps to get rid of the damaged cell. Some cells however escape this process by losing p53. The chromosomal instability together with the p53 loss initiates breast cancer formation. However, these cancers cannot grow very large because they have broken chromosomes. In the second step, cancer cells learn to reactivate telomerase to help fix their broken chromosomes and set them on an irreversible proliferative path. Specific aims: Our specific aims are 1. To study the role of short telomeres and defective p53 function in the onset of breast cancer. 2. To determine the effect of telomerase reactivation on breast cancer progression and 3. To study the role of telomere dysfunction in normal events which accompany mammary gland development, such as proliferation and survival. Study design: For the studies described in the proposal, we are creating a novel mouse model. In these mice, we are using a genetic trick to keep telomerase enzyme off and enable telomere shortening. We will also engineer these mice such that we can reactivate telomerase to study its effect on tumor progression by simple drug administration. We will use new technologies that enable us to examine broken chromosomes and also look at tumors in mice by imaging. Potential outcomes and benefits: The studies we propose here should be enormously useful towards understanding how telomerase can stabilize broken chromosomes and whether activating the enzyme before the formation of cancers can prevent breast cancer from developing. We hope that the findings from this study will enable us to better understand the events that drive breast cancer formation and aid in developing better preventive and therapeutic strategies.