Susan G Komen  
I've Been Diagnosed With Breast Cancer Someone I Know Was Diagnosed Share Your Story Join Us And Stay Informed Donate To End Breast Cancer
    Home > Research & Grants > Grants Program > Research Grants > Research Grants Awarded > Abstract

    Research Grants Awarded

    Mammary Cancer Stem Cells

    Study Section:
    Tumor Cell Biology V

    Scientific Abstract:
    Background. The cancer stem cell hypothesis proposes that a small population of tumor-initiating cancer stem cells (T-IC) exists within the heterogeneous population of cells in a malignancy. Normal stem cells or multipotent progenitor cells of the tissue in which the primary cancer arises are likely precursors of T-IC. Limitations on the definition and isolation of stem cells are a major obstacle to understanding T-IC. Parity-induced mammary epithelial cells (PI-MEC) self-renew and are pluripotent, and thus operate as mammary stem or progenitor cells. PI-MEC involvement in mammary cancer was reported, but a method to mark and isolate pure populations of PI-MEC was not described. Mammary tumors and preneoplastic changes are parity-induced in the C57BL/6J-Tg(WapTAg)1Knw (Waptag 1) mouse. Thus Waptag 1 is an attractive model in which to test the potential of marked PI-MECs as mammary tumor stem cells. Objective/hypothesis: The broad objective of this project is to understand the relationship between normal tissue stem cells and cancer stem cells in mouse models of mammary cancer. To test the hypothesis that mammary tumors in Waptag 1 arise from PI-MEC, I will develop mouse strains in which PI-MEC are fluorescently marked and can be purified for study. Specific Aims: 1. Develop control and Waptag1 mouse models with fluorescently labelled PI-MEC. 2. Characterize in vivo outgrowth properties of PI-MEC from control mice and from Waptag 1 mice. Study Design. Double transgenic control mice in which PI-MEC express enhanced green fluorescent protein will be derived by crossing B6-Cg-Tg(ACTB-Bgeo/GFP)21Lbe/J mice with B6-Cg-Tg(WapCre)11738Mam/J mice. These will then be crossed with Waptag 1 mice to develop a triple transgenic mouse mammary cancer model with fluorescently labelled PI-MEC. Properties of PI-MEC will be characterized in vivo using transplantation studies of mammary epithelial cells isolated by fluorescence activated cell sorting from control glands and from glands of mice at different stages in Waptag 1 tumorigenesis. Potential Outcomes and Benefits of the Research. Development of a mouse model of mammary cancer in which a defined cell population (PI-MEC) with properties of stem cells can be isolated and analyzed will enable (i) definition of the immunophenotype of different mammary tumor stem cells (ii) investigation of molecular events occurring in T-IC (iii) investigation of the general extent to which this cell population contributes to mammary cancer in other mouse models.

    Lay Abstract:
    Background: According to the cancer stem cell hypothesis, cancer stem cells initiate tumors. Over time these stem cells renew themselves, whilst giving rise to the cells which form the bulk of the cancer. The properties of cancer stem cells resemble normal tissue stem cells, from which they are thought to be derived. Understanding the relationship between normal tissue stem cells and cancer stem cells is important for understanding how cancers are initiated. Lack of means to identify and purify stem cells from normal tissues or from cancers is a major problem in the field. Parity-induced mammary epithelial cells (PI-MEC) (i.e. mammary cells whose formation is induced by pregnancy and lactation) behave as mammary gland stem cells, and are involved in mouse breast cancer. However there is no simple means of marking and isolating pure populations of PI-MEC for study. Parity-induced mammary cancers in C57BL/6J-Tg(WapTAg)1Knw (Waptag 1) mice, suggest Waptag1 mice might be ideal for studying normal and tumorigenic PI-MEC. Objective: My objective is to develop genetically modified mouse strains with fluorescent PI-MEC. This will enable detection, isolation and experimental manipulation of PI-MEC in normal and mammary tumor-prone mice. I will characterize the mouse strains developed by testing the hypothesis that PI-MEC are precursors of tumor stem cells in Waptag 1 mouse mammary tumors. Specific Aims: 1. Develop control and Waptag1 mouse models with fluorescent PI-MEC. 2. Characterize growth and tumor-forming properties of PI-MEC from control and Waptag 1 mice. Study Design: Two different existing strains of genetically modified mice will be bred together to generate a new mouse strain (DT) whose PI-MEC are fluorescent. DT mice will be bred to Waptag1 mice to generate a second new mouse strain (TT), prone to mammary cancer. Properties of PI-MEC will be tested by transplanting PI-MEC purified from DT (control) and TT into young mice, and analyzing the amount and type of mammary gland or tumor growth in the recipients. Potential Outcomes and Benefits of the Research. Mouse models of mammary cancer in which cells (PI-MEC) with stem cell properties can be purified and analyzed will enable (i) better identification of mammary tumor stem cells in the future (ii) investigation of molecular events changing normal stem cells to tumor stem cells. The general extent to which PI-MEC contribute to mammary cancer can be studied by crossing DT with other mouse mammary cancer models.