Remodeling of Endogenous Mammary Epithelium by Breast Cancer Stem Cells§

Authors

  • Natesh Parashurama,

    1. Molecular Imaging Program @Stanford, Department of Radiology, Division of Nuclear Medicine, Stanford University School of Medicine, Stanford, CA, USA
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    • Contributed equally to this work.

  • Neethan A. Lobo,

    1. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
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    • Contributed equally to this work.

  • Ken Ito,

    1. Molecular Imaging Program @Stanford, Department of Radiology, Division of Nuclear Medicine, Stanford University School of Medicine, Stanford, CA, USA
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  • Adriane R. Mosley,

    1. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
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  • Frezghi G. Habte,

    1. Molecular Imaging Program @Stanford, Department of Radiology, Division of Nuclear Medicine, Stanford University School of Medicine, Stanford, CA, USA
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  • Maider Zabala,

    1. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
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  • Bryan R. Smith,

    1. Molecular Imaging Program @Stanford, Department of Radiology, Division of Nuclear Medicine, Stanford University School of Medicine, Stanford, CA, USA
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  • Jessica Lam,

    1. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
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  • Irving L. Weissman,

    1. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
    2. Pathology, Stanford University School of Medicine Stanford, CA, USA
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  • Michael F. Clarke,

    1. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
    2. Internal Medicine (Oncology)Stanford University School of Medicine Stanford, CA, USA
    3. Program in Cellular and Molecular Biology, Stanford University School of Medicine, Stanford, CA, USA
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  • Sanjiv S. Gambhir

    Corresponding author
    1. Molecular Imaging Program @Stanford, Department of Radiology, Division of Nuclear Medicine, Stanford University School of Medicine, Stanford, CA, USA
    2. Canary Center for Early Detection of Cancer, Palo Alto, CA, USA
    3. Departments of BioengineeringStanford University School of Medicine Stanford, CA, USA
    4. Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA
    • Molecular Imaging Program @Stanford, Department of Radiology, Division of Nuclear Medicine, James H. Clark Center, Stanford University, 318 Campus Drive, E153, Stanford, CA 94305, USA

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    • Telephone: 650-725-2309; Fax: 650-724-4948


  • Author contributions: N.P., N.A.L, M.F.C, and S.S.G.: conceived of, conceptualized, the study. N.P. and N.A.L: designed the experiments. N.P. and N.A.L. performed in vivo experiments with help of J.L., A.R.M., M.Z., and K.I. N.P. and N.A.L. collected and assembled data, with help of K.I. and B.R.S.; N.P, N.L., and F.B.H.: performed data analysis and interpretation; S.S.G. and M.F.C.: provided financial support; N.P., N.A.L, S.S.G, and M.F.C.: wrote and revised the manuscript, with final approval by I.L.W. M.F.C., and S.S.G.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS August 16, 2012.

Abstract

Poorly regulated tissue remodeling results in increased breast cancer risk, yet how breast cancer stem cells (CSC) participate in remodeling is unknown. We performed in vivo imaging of changes in fluorescent, endogenous duct architecture as a metric for remodeling. First, we quantitatively imaged physiologic remodeling of primary branches of the developing and regenerating mammary tree. To assess CSC-specific remodeling events, we isolated CSC from MMTV-Wnt1 (mouse mammary tumor virus long-term repeat enhancer driving Wnt1 oncogene) breast tumors, a well studied model in which tissue remodeling affects tumorigenesis. We confirm that CSC drive tumorigenesis, suggesting a link between CSC and remodeling. We find that normal, regenerating, and developing gland maintain a specific branching pattern. In contrast, transplantation of CSC results in changes in the branching patterns of endogenous ducts while non-CSC do not. Specifically, in the presence of CSC, we identified an increased number of branches, branch points, ducts which have greater than 40 branches (5/33 for CSC and 0/39 for non-CSC), and histological evidence of increased branching. Moreover, we demonstrate that only CSC implants invade into surrounding stroma with structures similar to developing mammary ducts (nine for CSC and one for non-CSC). Overall, we demonstrate a novel approach for imaging physiologic and pathological remodeling. Furthermore, we identify unique, CSC-specific, remodeling events. Our data suggest that CSC interact with the microenvironment differently than non-CSC, and that this could eventually be a therapeutic approach for targeting CSC. STEM Cells2012;30:2114–2127

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