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    The Role of Altered Huntingtin Interacting Protein 1 (HIP1)Levels in the Biology of Breast Cancer

    Scientific Abstract:
    The Role of Altered Huntingtin Interacting Protein 1 (HIP1) Levels in the Biology of Breast Cancer Huntingtin Interacting Protein 1 (HIP1) is a clathrin and inositol lipid binding protein that may be involved in neurodegeneration by virtue of its interaction with huntingtin, the protein mutated in Huntington’s disease. It is also associated with leukemia by discovery of the oncogenic HIP1/PDGFbetaR fusion protein that resulted from a t(5;7) chromosomal translocation in a patient with chronic myelomonocytic leukemia. We think HIP1 may be involved in breast tumorigenesis for the following reasons. First, HIP1 is over-expressed in primary breast tumors (Bradley et al., 2003). Second, expression of a dominant negative mutant of HIP1 or genetic deletion of HIP1 leads to apoptosis (Rao et al., 2001) suggesting that expression of HIP1 may be necessary for survival of tumor cells. Finally, over-expression of HIP1 in NIH/3T3 cells leads to transformation and the upregulation of growth factor receptors (Bradley et al., 2003). The first hypothesis we propose to test is that HIP1 is tumorigenic and its over-expression in the breast in vivo leads to breast cancer. As a corollary, we predict that when HIP1 is not expressed in a mouse knockout model, there will be a diminished susceptibility to the development and/or progression of breast cancer. Second, we propose to test the hypothesis that other molecules functionally related to the HIP1 trafficking pathway are involved in the pathogenesis of breast cancer. The purpose of testing these hypotheses is that the identification of HIP1 or other molecules in the clathrin trafficking pathway as key players in the pathogenesis of breast cancer may ultimately result in more effective, less toxic breast cancer therapies. Specific aim #1: Test the hypothesis that HIP1 over-expression is sufficient for breast tumorigenesis in vivo. To generate mice with HIP1 over-expression in the breast epithelium, we plan to create tetracycline inducible transgenic mice. Mice will be observed for the development of obvious breast tumors in the presence of tetracycline, and routine necropsies will be performed on mice of various ages to monitor for breast tumor development internally. As a corollary, others in the lab will test if the Hip1 null background prevents the formation of breast tumors in mice that are transgenic mice expressing Myc or Her2 in the murine breast epithelium. Specific aim #2: Test the hypothesis that expression of the HIP1 family member, HIP1r, is altered in breast tumors. Since HIP1 and HIP1r share a similar domain structure and likely participate in clathrin mediated trafficking, we hypothesize that HIP1r has overlapping or opposing functions compared to HIP1. Another very likely candidate to test for a role in tumorigenesis that also colocalizes with HIP1 is Eps15 (Rao et al., 2001). Eps15 is an in vivo substrate of the EGFR and alters the growth of NIH/3T3 cells (Confalonieri et al, 2000). If such molecules such as HIP1r and Eps15 are over-expressed or under-expressed in breast tumors, we will then work to understand the mechanisms as to how their differential gain or loss of expression can influence to tumor formation or progression. Potential outcomes and benefits of the research: The accumulation of new data that would implicate HIP1 and other endocytic proteins in breast cancer biology would make an important point to the cancer field: that the endocytic pathway is a critical regulator of cell proliferation and that altered expression of regulatory proteins in that pathway can be oncogenic. We would like to test if the disruption of normal receptor traffic by HIP1 is sufficient for tumorigenesis and begin to determine if other proteins in the trafficking pathway also contribute to tumorigenesis when disrupted.

    Lay Abstract:
    The Role of Altered Huntingtin Interacting Protein 1 (HIP1) Levels in the Biology of Breast Cancer. HIP1 is a protein involved in protein trafficking that may be involved in neurology by virtue of its interaction with huntingtin, the protein mutated in Huntington’s disease. It is also associated with leukemia by its discovery as part of an oncogene in leukemia. We think that HIP1 is involved in breast cancer for the following reasons. First, HIP1 levels are elevated in breast tumors. Second, lack of HIP1 in a cell leads to cellular death, suggesting that expression of HIP1 may be necessary for survival of tumor cells. Third, over-expression of HIP1 leads to cancerous transformation of fibroblasts and alters the traffic patterns of proteins involved in breast cancer biology. The first hypothesis we propose to test is that HIP1 is sufficient to cause tumors when its levels are increased in the breasts of mice. As a corollary, we predict that when HIP1 is not present in the mouse, there will be a diminished susceptibility to the development or progression of breast cancer. Second, we will test the hypothesis that molecules that are structurally or functionally related to HIP1 also alter the traffic patterns of proteins implicated in breast cancer and thereby contribute to the formation and/or evolution of breast cancers.