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    Awarded Grants
    Role of the Heparin-Binding Growth Factor, Pleiotrophin, in Breast Cancer Motility and Invasion

    Scientific Abstract:
    It is well recognized that an integral part of the progression of breast cancer is the acquisition of the invasive and metastatic phenotype. This proposal examines the hypothesis that the receptor for the growth factor pleiotrophin (PTN) modulates the invasion and motility of breast cancer cells. This would establish the pleiotrophin receptor as a novel growth factor receptor for breast cancer. Pleiotrophin has previously been described as a mitogenic factor for fibroblasts and endothelial cells, both of which express the pleiotrophin receptor. However, we have identified aberrant expression of the receptor for this growth factor in a number of breast cancer cell lines and primary tumors. This discovery distinguishes a subset of tumors and cell lines where both pleiotrophin and its receptor are expressed. Previously it has been demonstrated that a number of classically mitogenic growth factor receptors can regulate invasion and motility via signaling pathways distinct from those initiated as part of the mitogenic response. Therefore, we predict that autocrine effects of pleiotrophin regulate not only tumor growth but also tumor cell behavior, and in particular cell motility and the invasive phenotype. In aim one, we will use ribozyme technology to decrease the levels of expression of the pleiotrophin receptor (ALK) in cell lines where we predict that autocrine effects of PTN modulate the invasive phenotype. This study will be performed in cell lines whose invasive phenotype in vitro have been well characterized both in our hands and those of other investigators. We predict that decreasing levels of the receptor will profoundly affect the invasive, motile and metastatic capacity of these cells. In aim two, we will introduce and overexpress the pleiotrophin receptor in a breast cancer cell line that normally has no endogenous expression of this growth factor receptor. This will provide a wealth of information about the potential of this receptor in terms of transformation effects from overexpression and ligand dependent and independent activation. We will also characterize motility and invasion in response to exogenously added pleiotrophin. These experiments will begin to elucidate the potential for transformation in breast cancer cells for this growth factor under conditions both dependent and independent of the presence of PTN. Finally, in aim three we will examine the role of paracrine signaling between PTN secreting tumor cells and the tumor stromal compartment. This will involve a detailed study of the cell migrational responses of endothelial cells. We will focus on the regulation of these processes as they contribute towards the process of tumor angiogenesis, the induction of new blood vessel growth in the tumor as a pathological process intimately involved with not only tumor growth but also invasion and the metastatic process. In summary, this study will begin to elucidate the potential of the PTN-R as a critical growth factor receptor for breast cancer progression, particularly regarding its involvement in the invasive phenotype. We will examine whether the PTN receptor ALK represents a novel prognostic factor for breast cancer. Furthermore characterization of the role of this receptor in breast cancer may also identify ALK as a novel therapeutic target for this disease.

    Lay Abstract:
    It is well recognized that the progression of breast cancer requires the acquisition of an invasive and metastatic phenotype. Identification of key molecules in the molecular pathways that provide a regulatory step in this progression can therefore lead to the identification of markers that represent not only prognosticators for progression of the disease but may also represent therapeutic targets. This proposal examines the hypothesis that the receptor for the growth factor pleiotrophin (PTN) is one of these critical regulatory molecules. We predict that molecular signaling mediated by PTN via its tyrosine kinase receptor, anaplastic lymphoma kinase (ALK), modulates invasion, motility and the metastatic potential of breast cancer. Furthermore, PTN is an angiogenic factor, stimulating new blood vessel growth in a tumor. This process requires not only mitogenesis, but also the migration of stromal cells towards and into the tumor. Therefore, we suggest that PTN also stimulates migration and motility in fibroblasts and endothelial cells, contributing towards the process of angiogenesis. In aims one and two we will modulate the expression levels of the PTN receptor. We predict that decreased expression of ALK in breast cancer cell lines where both ALK and PTN are highly expressed will lead to a decrease in the invasive and metastatic capacity of aggressive breast cancer cell lines. We will also express ALK in breast derived cell lines that do not normally express this receptor. We will examine how this aberrant expression affects these cell lines in terms of their invasive and metastatic capacity. Finally, in aim 3 we will examine the effects of signaling via the PTN-ALK axis in normal untransformed cells. In particular we will focus on endothelial cells that participate in the induction of new blood vessel growth into the tumor in response to PTN. This response requires migration of these cells into the tumor. In summary, this study will begin to elucidate the potential of ALK as a critical growth factor receptor for breast cancer progression, particularly regarding its involvement in the invasive and metastatic phenotype. We will examine ALK represents a novel prognostic factor for breast cancer. Furthermore characterization of the role of this receptor in breast cancer may also identify this growth factor receptor as a novel therapeutic target for this disease.