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    Research Grants Awarded

    Emi1 Overexpression in Mouse Mammary Gland and Human Breast Cancer

    Study Section:
    Postdoctoral Fellowship

    Scientific Abstract:
    While the past few decades have witnessed major progress in the screening and treatment of breast cancer, de novo or acquired resistance to existing breast cancer drugs is a significant problem. Much is known about the role of cell cycle regulators upstream of the retinoblastoma (Rb) pathway in mammary tumorigenesis, but how misregulation of cell cycle regulators directly downstream of the Rb pathway causes or contributes to breast cancer development remains essentially obscure. Overexpression of Emi1, an inhibitor of the anaphase-promoting complex (APC), correlates with poor breast cancer prognosis and causes aberrant cell cycle entry and multiple mitotic defects that lead to genomic instability in vitro. However, the in vivo relevance of these observations is unclear. Therefore, I propose to conditionally overexpress Emi1 in mammary epithelial cells (MECs) using a transgenic mouse model. MECs from these mice will be cultured in vitro to investigate whether these cells acquire cell cycle checkpoint defects and genomic instability. In addition, I will study the expression of Emi1 and several tumor suppressor genes in a large number of human breast tumor tissues using tissue micro-arrays. The transgenic mice will be used to examine genetic interactions between Emi1, the Rb and Her2/neu pathways and Mad2, another APC inhibitor involved in the mitotic checkpoint. Exploring the role of APC inhibitors downstream of the Rb pathway may eventually lead to the discovery of novel therapeutic targets for breast cancer.

    Lay Abstract:
    While the past few decades have witnessed major progress in the screening and treatment of breast cancer, resistance to existing breast cancer drugs is a significant problem. The development of new drugs requires a better understanding of how breast cancer develops. The Emi1 protein is involved cell division. In a normal, non-dividing cell, Emi1 protein levels are low. In response to growth stimuli, Emi1 levels increase and this causes the cell to start dividing. Breast tumor cells are characterized by high levels of Emi1, but it is not clear whether this directly causes uncontrolled cell division or whether this is merely a consequence of another defect that occurred prior to the establishment of high Emi1 levels. To investigate this, I will introduce high Emi1 levels in the mammary cells of mice and study whether this leads to tumor formation. I will also assess if these mammary cells acquire genetic abnormalities. In addition, I will study the interactions between Emi1 and other cell division regulators involved in breast cancer development in both mammary cells from mice and human breast tumor tissues. Research on Emi1 and related regulators of cell division is crucial for the development of novel, potentially more effective drugs for breast cancer treatment.