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[Cancer Research 66, 6063-6071, June 15, 2006]
© 2006 American Association for Cancer Research

Molecular Biology, Pathobiology, and Genetics

Hedgehog Signaling and Bmi-1 Regulate Self-renewal of Normal and Malignant Human Mammary Stem Cells

Suling Liu, Gabriela Dontu, Ilia D. Mantle, Shivani Patel, Nam-shik Ahn, Kyle W. Jackson, Prerna Suri and Max S. Wicha

Comprehensive Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan

Requests for reprints: Max S. Wicha, Comprehensive Cancer Center, Department of Internal Medicine, University of Michigan, Room 7110, 1500 East Medical Center Drive, 6303 CCGC, Ann Arbor, MI 48109-0946. Phone: 734-936-1831; Fax: 734-615-3947; E-mail: mwicha{at}med.umich.edu.

The epithelial components of the mammary gland are thought to arise from stem cells with a capacity for self-renewal and multilineage differentiation. Furthermore, these cells and/or their immediate progeny may be targets for transformation. We have used both in vitro cultivation and a xenograft mouse model to examine the role of hedgehog signaling and Bmi-1 in regulating self-renewal of normal and malignant human mammary stem cells. We show that hedgehog signaling components PTCH1, Gli1, and Gli2 are highly expressed in normal human mammary stem/progenitor cells cultured as mammospheres and that these genes are down-regulated when cells are induced to differentiate. Activation of hedgehog signaling increases mammosphere-initiating cell number and mammosphere size, whereas inhibition of the pathway results in a reduction of these effects. These effects are mediated by the polycomb gene Bmi-1. Overexpression of Gli2 in mammosphere-initiating cells results in the production of ductal hyperplasia, and modulation of Bmi-1 expression in mammosphere-initiating cells alters mammary development in a humanized nonobese diabetic-severe combined immunodeficient mouse model. Furthermore, we show that the hedgehog signaling pathway is activated in human breast "cancer stem cells" characterized as CD44+CD24–/lowLin–. These studies support a cancer stem cell model in which the hedgehog pathway and Bmi-1 play important roles in regulating self-renewal of normal and tumorigenic human mammary stem cells. (Cancer Res 2006; 66(12): 6063-71)




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