ROLES OF PLEIOTROPHIN IN NORMAL AND ABNORMAL CELL GROWTH

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Pleiotrophin (PTN) is a heparin-binding protein that functions as a weak mitogen with fibroblasts and brain capillary endothelial cells. It also induces process outgrowth and apparent differentiation with neuronal and glial progenitors. The ptn gene is a member of the platelet-derived growth factor (PDGF) induced early response cytokine genes and may mediate some of the normal functions of PDGF by autocrine or paracrine mechanisms. PTN also is transforming when its gene is overexpressed in NIH 3T3 cells. High levels of its expression have been found in mammary tumor cells and primary human breast tumors. Analysis of the functions of PTN in tumors thus may contribute to understanding both normal and abnormal cell growth. Furthermore, analysis of its ability to cooperate with other oncogenes offers a unique opportunity to study genetic pathways of tumorigenesis. Preliminary data are presented to establish that the PTN gene under control of the mouse mammary tumor virus (MMTV) promoter partially transforms mouse mammary epithelial cells. We plan to further study the potential of the ptn gene as a transforming gene in mouse mammary epithelial cells and as a transgene in mice. Its potential to cooperate with loss-of-function of tumor suppressor genes such as MMTV-p53 and gain-of-function of growth related genes such as MMTV-c-myc and MMTV-TGF- alpha to induce mammary tumors, and to enhance the aggressiveness of MMTV-c-neu induced mammary tumors in transgenic mice will be tested by cross-breeding MMTV-PTN mice with other MMTV-transgenic mice. It is also proposed to use mouse mammary epithelial cells to delineate functional (heparin binding, active site) domains of PTN that are required for its role in partial transformation by mutational analysis. The heparin binding mutants that are defined will be used to test the importance of binding of PTN to the extracellular matrix and/or cell surface for process outgrowth and in transformation. The active site mutants to be defined will be tested for loss of transforming potential in vitro, in the nude mouse, and for loss of ability to support process outgrowth of cells in cultures to determine if the same domaine mediates each of these activities. Appropriate functional mutants then will be expressed with MMTV in transgenic mice and tested alone and/or with cooperating genes by breeding to other MMTV transgenic mice. The results of this work will provide important new information on the functional roles of PTN, on its functional domains. It should direct strategies to alter the function of PTN in breast cancer and may advance understanding of the genetic basis of breast cancer in humans.