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CANCER STEM CELLS

Isolation and Molecular Characterization of Cancer Stem Cells in MMTV-Wnt-1 Murine Breast Tumors

Departments of ^aPediatrics,
^dStatistics, and
^eInternal Medicine and
^gProgram in Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, Michigan, USA;
^bOncomed Pharmaceuticals Inc., Redwood City, California, USA;
Departments of ^cRadiation Oncology and
^fGenetics, Stanford University, Palo Alto, California, USA;
^hStanford Institute for Stem Cell Biology and Regenerative Medicine, Palo Alto, California, USA

Key Words. Wnt-1 • Cancer stem cell • Breast cancer • Murine

Correspondence: Michael F. Clarke, M.D., Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Palo Alto, California, 94304, USA. Telephone: 650-725-2495; Fax: 650-736-2961; e-mail: mfclarke{at}stanford.edu

Received June 6, 2007; accepted for publication October 17, 2007.
First published online in STEM CELLS EXPRESS   November 1, 2007.



In human breast cancers, a phenotypically distinct minority population of tumorigenic (TG) cancer cells (sometimes referred to as cancer stem cells) drives tumor growth when transplanted into immunodeficient mice. Our objective was to identify a mouse model of breast cancer stem cells that could have relevance to the study of human breast cancer. To do so, we used breast tumors of the mouse mammary tumor virus (MMTV)-Wnt-1 mice. MMTV-Wnt-1 breast tumors were harvested, dissociated into single-cell suspensions, and sorted by flow cytometry on Thy1, CD24, and CD45. Sorted cells were then injected into recipient background FVB/NJ female syngeneic mice. In six of seven tumors examined, Thy1+CD24+ cancer cells, which constituted approximately 1%–4% of tumor cells, were highly enriched for cells capable of regenerating new tumors compared with cells of the tumor that did not fit this profile ("not-Thy1+CD24+"). Resultant tumors had a phenotypic diversity similar to that of the original tumor and behaved in a similar manner when passaged. Microarray analysis comparing Thy1+CD24+ tumor cells to not-Thy1+CD24+ cells identified a list of differentially expressed genes. Orthologs of these differentially expressed genes predicted survival of human breast cancer patients from two different study groups. These studies suggest that there is a cancer stem cell compartment in the MMTV-Wnt-1 murine breast tumor and that there is a clinical utility of this model for the study of cancer stem cells.

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