Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology*
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Female
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Hedgehog Proteins
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Humans
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Kruppel-Like Transcription Factors / biosynthesis
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Kruppel-Like Transcription Factors / genetics
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Mammary Glands, Human / cytology
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Mammary Glands, Human / metabolism
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology*
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Nuclear Proteins / biosynthesis
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Oncogene Proteins / genetics
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Oncogene Proteins / metabolism
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Polycomb Repressive Complex 1
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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RNA, Small Interfering / genetics
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Repressor Proteins / biosynthesis
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Signal Transduction
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Trans-Activators / agonists
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Trans-Activators / antagonists & inhibitors
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Trans-Activators / metabolism*
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transplantation, Heterologous
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Zinc Finger Protein GLI1
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Zinc Finger Protein Gli2
Substances
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BMI1 protein, human
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Gli2 protein, mouse
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Hedgehog Proteins
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Kruppel-Like Transcription Factors
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Nuclear Proteins
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Oncogene Proteins
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Proto-Oncogene Proteins
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RNA, Small Interfering
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Repressor Proteins
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Trans-Activators
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Transcription Factors
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Zinc Finger Protein GLI1
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Zinc Finger Protein Gli2
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Polycomb Repressive Complex 1