Contributed equally to this work.
Cancer Stem Cells
Version of Record online: 20 SEP 2012
Copyright © 2012 AlphaMed Press
Volume 30, Issue 10, pages 2114–2127, October 2012
How to Cite
Parashurama, N., Lobo, N. A., Ito, K., Mosley, A. R., Habte, F. G., Zabala, M., Smith, B. R., Lam, J., Weissman, I. L., Clarke, M. F. and Gambhir, S. S. (2012), Remodeling of Endogenous Mammary Epithelium by Breast Cancer Stem Cells. STEM CELLS, 30: 2114–2127. doi: 10.1002/stem.1205
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.
- Issue online: 20 SEP 2012
- Version of Record online: 20 SEP 2012
- Accepted manuscript online: 16 AUG 2012 03:22PM EST
- Manuscript Accepted: 3 JUL 2012
- Manuscript Received: 30 JAN 2012
- NCI ICMIC. Grant Number: P50CA114747
- Canary Foundation
- Stanford Dean's Fellowship
- Stanford NIBIB T32 Training. Grant Number: EB009035
- Stanford Neuroscience Microscopy Service (NIS)
- Two-Photon Microscope
- Cancer stem cells;
- Intravital microscopy;
- Breast cancer;
- Molecular imaging;
- Mammary stem cells
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