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    Role of Separase in Breast Cancer

    Scientific Abstract:
    Background: Karyotypic changes manifested as abnormal chromosome numbers (aneuploidy) are a hallmark of breast cancer. Recent studies indicate that steroid hormones can significantly increase aneuploidy status and lead to breast cancer in a mouse model deficient in the tumor suppressor gene p53. This murine model of hormone-induced aneuploidy in p53-deficient mammary cells may provide a critical link between hormonal status, p53 mutation, aneuploidy, and breast cancer, and may help to define underlying molecular mechanisms of breast cancer pathogenesis and identify targets for therapeutic intervention. Objective/Hypothesis: The proposal will address an important question of how loss or mutation of p53 facilitates steroid hormones-induced aneuploidy typically associated with human breast cancer. Based on our novel preliminary data we hypothesize that there is a set of proteins whose misregulation promotes aneuploidy (termed PRAN, Promoter of Aneuploidy) as determined by aneuploidy status, and that PRANs are combinatorially regulated by steroid hormones and tumor suppressor p53. The hypothesis to be tested in this proposal is that hormonal stimulation of p53 null mice mammary gland results in misexpression of ESPL1 gene (encodes Separase protein), a key chromosomal segregation protein and a candidate PRAN leading to aneuploidy. Specific Aims: 1) Characterize the functional role of constitutionally over-expressed Separase in aneuploidy, and 2) Generate a transgenic mouse model for conditional ectopic expression of Separase in the mammary gland to further examine the role of Separase in mammary carcinogenesis. Study Design: The functional significance of changes in the expression of Separase cDNA/protein in the generation of aneuploidy and overall role of Separase in mammary carcinogenesis will be studied by using two approaches: 1) in vivo Medina mammary transplant model for constitutional expression of Separase, and 2) development of a transgenic mouse models for conditional ectopic expression of Separase in the mammary gland. Outcome: Understanding the role of p53 and steroid hormone signaling in relation to the mitotic checkpoint and sister chromatid cohesion proteins is novel and will provide a link between steroid-induced chromosomal instability, p53 mutation and aneuploidy. Identification of these pathways would provide a valuable mechanistic understanding of the pathways involved in initiation and progression of breast cancer.

    Lay Abstract:
    Background: This application focuses on 3 vital aspects of breast cancer pathogenesis: 1)hormone (progesterone/estrogen) exposure, which is a well characterized risk for the development of human breast cancers, 2)the mutation or deletion of p53 tumor suppressor protein, which occurs in 30-50% of breast cancers, and 3)aneuploidy (abnormal chromosome number), which is seen in up to 70% of breast cancers. We propose to utilize a murine model by the Medina lab that integrates these 3 aspects of human breast cancer: hormonal exposure rapidly increases aneuploidy that precedes formation of tumors in mammary epithelium derived from p53 null mice. Thus this mouse system is an innovative model for studying pathogenesis of human breast cancer in rodents. Objective/Hypothesis: The goal of this project is to understand how loss or mutation of p53 facilitates hormone-induced aneuploidy by identifying molecules that promotes aneuploidy (we call them Promoters of Aneuploidy, PRAN in short). We hypothesize that aneuploidy can arise when there is a defect in the mechanisms that ensure faithful segregation of chromosomes between two newly divided cells, and that hormonal steroids play a critical role in the regulation of mechanisms that act as a brake to stop cell division when a cell’s genetic material becomes damaged. Specific Aims: 1) Characterize the functional role of Separase, a chromosomal segregation protein in aneuploidy, and 2) Generate a Separase transgenic mouse model to examine its role in mammary carcinogenesis. Study Design: Role of Separase in mammary carcinogenesis will be studied by using two approaches: 1) in vivo Medina mammary transplant model for constitutional expression of Separase, and 2) development of a transgenic mouse for conditional expression of Separase in the mammary gland. These two models will evaluate the direct role of Separase in the development of aneuploidy that precedes tumor formation in mammary gland. These models will also examine if steroidal hormone and p53 mutation drives the process of aneuploidy by influencing Separase expression. Outcome: Aneuploidy is a common feature of breast cancer and is associated with poor prognosis. As steroid hormones play a role in the risk and progression of breast cancer, the proposal that hormonal stimuli may act directly on specific genes and protein complexes involved in chromosomal segregation represents a novel mechanism. Identification of these pathways would provide valuable mechanistic understanding of the pathways involved in initiation and progression of breast cancer.