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    Research Grants Awarded

    The role of Gpr125 in breast stem/progenitor cells

    Study Section:
    Postdoctoral Fellowship

    Scientific Abstract:
    The contribution of stem cells to the development of breast cancer is an intriguing and controversial hypothesis. The latency of breast cancer has led to the proposal that stem cells are the only cells long-lived enough to accrue the necessary mutations predisposing to carcinogenesis. It is unclear whether the "cancer stem cell" originates from a stem cell, a progenitor cell of more limited potential, or a differentiated cell that has acquired "stem-like" capabilities. The basic functional properties of normal breast stem cells have yet to be fully uncovered and the mammary lineage progression is poorly understood. Thus, a major limitation to the study of breast cancer remains the incomplete characterization of stem and progenitor cells in the breast. The goal of this proposal is to establish the role of a novel orphan G protein-coupled receptor, Gpr125, in the pool of activated breast stem/progenitor cells. As Gpr125 was discovered only recently, its physiological role in any tissue remains elusive. Employing a LacZ knock-in reporter mouse of Gpr125, my preliminary data reveal that Gpr125 is expressed in sites within the mammary gland enriched in activated stem/progenitor cells. This expression pattern implicates Gpr125 in the biology of breast stem/progenitor cells at precisely the time that they are stimulated to proliferate to yield differentiated progeny that form ducts and alveoli. Consistent with this hypothesis, my results show that homozygous deletion of Gpr125 results in a delayed ductal extension phenotype in the pubertal mammary gland. Exploiting the Gpr125-lacZ reporter mouse, the first specific aim of my proposal seeks to validate the cell type expressing Gpr125 as an activated stem/progenitor cell. My second aim will further assess mammary gland and mammary stem/progenitor cell phenotypes caused by Gpr125 loss. I will examine the mechanism of Gpr125 as a regulator of cell-cell communication through its involvement with cell junctions in my third aim. My final aim explores the role of Gpr125 as a moderator of the cancer phenotype. Cells isolated from mammary glands of Gpr125-lacZ mice will be examined for expression of characteristic surface markers of mammary stem cells. The potential for Gpr125-positive cells to display stem-like capabilities will be assessed by self-renewal and regeneration assays, as well as 3-dimensional tissue culture methods. The contribution of Gpr125 to breast tumorigenesis will be assessed using mouse models in which the incipient tumors harbor populations of stem or progenitor cells. These analyses will provide insight into the role for Gpr125 in the regulation and activation of breast stem/progenitor cells. Significantly, examination of Gpr125 function within this critical population of cells will provide insight into the basic processes of stem/progenitor cells, and in turn, will enhance our understanding of the fundamental role of stem/progenitor cells in tumorigenesis.

    Lay Abstract:
    In recent years, the role of cancer stem cells in the development of breast cancer has gained support. Although this hypothesis remains controversial, evidence is mounting that lends credence to the idea that stem cells and their immediate progenitors may be preferential targets for mutation and tumorigenic transformation. However, a true understanding of the contribution of cancer stem cells to breast cancer is lagging because the basic fundamental properties of normal stem cells or their offspring, which have a more limited regenerative potential, have yet to be fully explored. The goal of this proposal is to determine the role of a novel cell surface receptor, Gpr125, as a unique mediator of breast stem/progenitor cell activation. As Gpr125 was discovered only recently, its physiological role in any tissue remains elusive. Utilizing a reporter mouse model to examine the expression pattern of Gpr125 in the mouse mammary gland, my preliminary data reveal that Gpr125 is expressed in sites enriched in stem/progenitor cells that are actively dividing. This expression pattern suggests a role for Gpr125 in the biology of breast stem/progenitor cells that are stimulated to divide and differentiate during formation of the pubertal ductal tree and during subsequent pregnancy-induced cyclical breast remodeling. Consistent with this hypothesis, my results show that loss of Gpr125 results in a delayed outgrowth of ducts in the mammary gland during pubertal development. In this proposal, I will use the Gpr125 reporter mouse to isolate cells based on their cell surface marker expression and validate that the cell type expressing Gpr125 is a stem or progenitor cell. I will assess whether or not loss of Gpr125 results in a failure of stem/progenitor cells to function properly. In addition, I will examine the ability of Gpr125 to regulate communication between cells through its involvement with cell junctions. Finally, I will explore the role of Gpr125 as a moderator of tumor development in the mouse. These analyses will provide insight into the role for Gpr125 in the regulation and activation of breast stem/progenitor cells. Examination of Gpr125 function within this critical population of cells will illuminate the basic processes of stem/progenitor cells, and in turn, will enhance our understanding of the fundamental role of stem/progenitor cells in tumorigenesis.