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

¹ Department of Pediatrics, Ann Arbor, Michigan, 48109-0936
² Oncomed Pharmaceuticals Inc., Redwood City, CA 94063
³ Department of Radiation Oncology, Palo Alto, CA, 94304-1334.
⁴ Department of Statistics, Ann Arbor, Michigan, 48109-0936
⁵ Department of Internal Medicine, Ann Arbor, Michigan, 48109-0936
⁶ Department of Genetics, Palo Alto, CA, 94304-1334.
⁷ Department of Internal Medicine, Program in Cellular and Molecular Biology, Ann Arbor, Michigan, 48109-0936; Stanford University, Palo Alto, CA and Stanford Institute for Stem Cell Biology and Regenerative Medicine, Palo Alto, CA, 94304-1334.

^* To whom correspondence should be addressed. E-mail: mfclarke{at}stanford.edu.

	Abstract

In human breast cancers, a phenotypically distinct minority population of tumorigenic cancer (TG) 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 studying human breast cancer. To do so, we utilized breast tumors of the 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 FBV/NJ female syngeneic mice. In 6 of 7 tumors examined, Thy1+CD24+ cancer cells, which constituted approximately 1-4% of tumor cells were highly enriched for cells capable of regenerating new tumors when compared to cells of the tumor that did not fit this profile ("Not Thy1+CD24+"). Resultant tumors were of similar phenotypic diversity as 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.

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