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    Awarded Grants
    Disregulation of Stem Cell Self-renewal in Breast Cancer Development

    Scientific Abstract:
    It has been suggested that human breast cancers may arise from transformation of early stem and progenitor cells. However, studies to demonstrate this have been difficult to perform since mammary stem cells have not yet been isolated or characterized. Although the existence of stem cells in mouse mammary gland has been suggested by serial transplantation studies, the isolation and characterization of mammary stem cells has been limited by the lack of defined surface markers and culture systems to maintain these cells in an undifferentiated state. We have recently developed an in vitro culture system in which human mammary epithelial cells (HMEC) can be cultured in suspension as "mammospheres" highly enriched in stem and progenitor cells. We have utilized these systems to assess the effects of exogenous factors on stem cell self-renewal and differentiation. The Hedgehog pathway is essential for numerous processes during embryonic development, and this pathway remains active in normal brain and skin stem cells. Bmi-1 is a member of the polycomb gene family that functions as a transcriptional repressor and is involved in hematopoietic and neuronal stem cell self-renewal. We hypothesize that mammary stem cells are key targets of transformation resulting from the disregulation of processes that control self-renewal and differentiation of normal stem and progenitor cells. We postulate the involvement of self-renewal pathways common to other stem cells, including Hedgehog and Bmi-1. Our specific aims are: 1) to study the role of Hedgehog and Bmi-1 in normal human mammary stem cells self-renewal in vitro. 2) to determine whether over-expression or inhibition of genes involved in Hedgehog pathways and Bmi-1 pathway will modulate mammary stem cells self-renewal in vitro. 3) to determine whether overexpression of genes involved in Hedgehog or Bmi-1 signaling will induce the transformation of human mammary stem cells in an in vivo NOD-SCID model. We will utilize our newly developed culture system to elucidate Hedgehog and Bmi-1 signaling pathways. The effects of overexpression or inhibition of these pathways on self-renewal and differentiation of mammary stem cells will then be tested in these model systems. These studies should help elucidate the role of Hedgehog and Bmi-1 signaling pathways in regulating cell fate determination of human mammary stem cells and their role in mammary carcinogenesis. Furthermore, since "tumor stem cells" may drive carcinogenesis, the identification of pathways that regulate key processes in these cells may lead to more effective therapies.

    Lay Abstract:
    Stem cells are specialized cells that continually generate progeny cells for organ formation and maintenance. Stem cells can be found within the different tissues of the human body at all stages of life, before and after birth. It has recently been suggested that human breast cancers may arise from transformation of early stem and progenitor cells. However, studies to demonstrate this have been difficult to perform, since rodent or human mammary stem cells have not yet been isolated or characterized. The isolation and characterization of human mammary stem cells and the elucidation of the mechanisms governing self-renewal (renewing themselves indefinitely) and differentiation (producing cell progeny that mature into more specialized, organ-specific cells) could offer important insights into normal mammary differentiation and tumor formation. Although the existence of a stem cell population in the mouse mammary gland has been suggested, the isolation and characterization of mammary stem cells has been limited by the lack of defined surface markers and the lack of culture systems to maintain these cells in an undifferentiated state. We have developed a novel in vitro culture system in which human mammary epithelial cells (HMECs) can be cultured in suspension as ¡°mammospheres¡± highly enriched in mammary stem and progenitor cells, and we have utilized these systems to assess effects of exogenous factors on stem cell self-renewal and lineage specific differentiation. We postulate the involvement of self-renewal pathways common to other stem cells, including hedgehog and Bmi-1, both of which have been recently shown to be involved in the self-renewal of some adult stem cells. We propose to utilize our new culture system to elucidate the role of hedgehog and Bmi-1 pathways involved in cell fate determination of human mammary stem cells. We also propose to examine the effects of stimulation of these pathways on self-renewal in vitro and on the transformation of human mammary stem cells in an in vivo NOD (non-obese diabetic)/SCID mouse model. These studies should help elucidate the role of Hedgehog and Bmi-1 signaling pathways in regulating cell fate determination of human mammary stem cells and their role in mammary tumor formation. Furthermore, since "tumor stem cells" may drive tumor formation, the identification of pathways that regulate key processes in these cells may lead to more effective therapies.