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    Research Grants Awarded

    Bmi-1 and Epigenetic Mechanisms in Breast Cancer Stem Cells

    Study Section:
    Postdoctoral Fellowship

    Scientific Abstract:
    Background: Despite the current success of detecting and treating primary non-metastatic breast cancers, twenty percent of women die within 10 years of initial diagnosis of breast cancer. According to the cancer stem cell (CSC) hypothesis, the cells giving rise to these drug-resistant breast cancers may be of stem cell (SC) origin. Current cancer therapies target highly proliferative cancer cells and molecular alterations that occur in cells that make up the bulk of a solid tumor but not in the quiescent CSC. Consequently, tumor size is reduced, but aberrant CSC remain to regenerate tumors and metastatic lesions. To treat this disease, it is imperative that we identify unique molecular features that define CSC. Using fluorescence-activated cell sorting for cell surface markers, our laboratory has recently identified a small subpopulation of cancer-initiating cells from a well-characterized p53 null mouse model, which mimics a subset of human breast cancer. Several signaling pathways that regulate normal stem cell (NSC) self-renewal are implicated in carcinogenesis, indicating that deregulation of self-renewal may be a critical step in cancer development. Bmi-1 is an integral component of the Polycomb repressive complex-1, which represses transcription by stable silencing of target genes through chromatin modifications. Bmi-1?s maintenance of SC self-renewal in multiple tissues has important implications for epigenetic mechanisms in CSC. Objective/Hypotheis: Increased Bmi-1 activity allows p53 null breast CSC to evade the mechanisms that tightly limit self-renewal of NSC by deregulation of target genes through aberrant epigenetic regulation. Specific Aims/Study Design: 1) To determine whether expression of Bmi-1 and Bmi-1-regulatable genes is deregulated in p53 null cancer SC, gene expression analysis of tumor subpopulations will be carried out by quantitative real time RT-PCR and immunohistochemistry; 2) To determine whether manipulation of Bmi-1 expression alters the stem-like properties of p53 null cancer cells, tumor cells with either Bmi-1 loss of function or gain of function will be utilized for mammosphere, clonogen, and transplantation studies. Gain-of-function assays for Bmi-1-repressible genes combined with Bmi-1 suppression will be used to identify targets that deregulate CSC homeostasis; 3) To identify unique epigenetic features in p53 null CSC that distinguish CSC from non-tumorigenic subpopulations, genome-wide mapping of target genes for Polycomb chromatin-modifying proteins will be carried out. Potential Outcomes and Benefits of the Research: Ultimately, these studies will identify unique features of CSC that may provide novel therapeutic targets for drug-resistant CSC causing tumor recurrence and metastasis.

    Lay Abstract:
    Recent research supports a shift in the way we study cancer and design therapies. Despite the current success of detecting and treating primary non-metastatic breast cancers, 20% of women die within 10 years of initial diagnosis of breast cancer. The cells giving rise to these drug-resistant breast cancers may be of stem cell (SC) origin. The cancer stem cell (CSC) hypothesis postulates that a small percentage of cells that make up a tumor are the cancer-initiating cells. These CSC have the capacity to self-renew, or regenerate themselves, throughout the patient?s lifespan and to generate the other more differentiated cells that make up a tumor. Unfortunately, current cancer therapies target highly proliferative cancer cells that make up the bulk of a solid tumor but not the quiescent CSC. Consequently, tumor size is reduced, but aberrant CSC remain to regenerate tumors and metastatic lesions. To treat this disease, it is imperative that we identify unique molecular features that define CSC. Our laboratory has recently identified a small subpopulation of cancer-initiating cells from a well-characterized p53 null mouse model, which mimics a subset of human breast cancer. The p53 gene is one of the most often mutated or deregulated genes in cancer, thus it is critical to understand mechanisms underlying cancers that harbor p53 mutations or deletions. In the current proposal, we present multiple approaches to identify the unique characteristics of the SC population identified in the p53 null mouse model. Initially, these studies focus on identification of pathways that regulate SC self-renewal, and then they will address how these pathways regulate CSC properties with emphasis on epigenetic mechanisms. Epigenetic modifications regulate gene expression through several mechanisms including: DNA methylation of promoters, microRNA silencing, and histone modifications. Ultimately, these studies will identify unique features of CSC that may provide novel therapeutic targets for drug-resistant CSC causing tumor recurrence and metastasis.