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PMID: 16778178 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells.

Cancer research ·Vol. 66 ·No. 12 ·2006-06-15 ·Pages 6063-71

Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW, Suri P, Wicha MS

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.

MeSH Terms
Animals Breast Neoplasms/genetics,metabolism,pathology Female Hedgehog Proteins Humans Kruppel-Like Transcription Factors/biosynthesis,genetics Mammary Glands, Human/cytology,metabolism Mice Mice, Inbred NOD Mice, SCID Neoplastic Stem Cells/metabolism,pathology Nuclear Proteins/biosynthesis,genetics,metabolism Oncogene Proteins/genetics,metabolism Polycomb Repressive Complex 1 Proto-Oncogene Proteins/biosynthesis,genetics,metabolism RNA, Small Interfering/genetics Repressor Proteins/biosynthesis,genetics,metabolism Signal Transduction Trans-Activators/agonists,antagonists & inhibitors,metabolism Transcription Factors/genetics,metabolism Transplantation, Heterologous Zinc Finger Protein GLI1 Zinc Finger Protein Gli2
Chemicals
BMI1 protein, human Gli2 protein, mouse Hedgehog Proteins Kruppel-Like Transcription Factors Nuclear Proteins Oncogene Proteins Proto-Oncogene Proteins RNA, Small Interfering Repressor Proteins Trans-Activators Transcription Factors Zinc Finger Protein GLI1 Zinc Finger Protein Gli2 Polycomb Repressive Complex 1
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Liu Suling
Comprehensive Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109-0946, USA.
Dontu Gabriela
Mantle Ilia D
Patel Shivani
Ahn Nam-shik
Jackson Kyle W
Suri Prerna
Wicha Max S
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Article Info
Journal
Cancer research
Abbr.
Cancer Res
ISSN
0008-5472
DOI
10.1158/0008-5472.CAN-06-0054
Published
2006-06-15
Pages
6063-71
Language
English
Region
United States
NLM ID
2984705R
PMCID
PMC4386278
Subset
IM
Grants
NCI NIH HHS · R01 CA129765 · United States
NCI NIH HHS · P30 CA046592 · United States
NCI NIH HHS · R01 CA101860 · United States
NCI NIH HHS · CA101860 · United States
NCI NIH HHS · 5 P 30 CA46592 · United States
External Links
PubMed source DOI: 10.1158/0008-5472.CAN-06-0054 PMC Full Text View journal details
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