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Nat Commun. 2015 Apr 24;6:6910. doi: 10.1038/ncomms7910.

DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis.

Author information

1
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.
2
System Biology Section, Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
3
Department of Orthopedic Surgery, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.
4
Department of Pathology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.
5
1] Department of Biostatistics, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA [2] Cancer Research Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.
6
1] Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA [2] Cancer Research Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.
7
Cancer Research Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.
8
1] Department of Pathology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA [2] Cancer Research Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.

Abstract

Mammary stem/progenitor cells (MaSCs) maintain self-renewal of the mammary epithelium during puberty and pregnancy. DNA methylation provides a potential epigenetic mechanism for maintaining cellular memory during self-renewal. Although DNA methyltransferases (DNMTs) are dispensable for embryonic stem cell maintenance, their role in maintaining MaSCs and cancer stem cells (CSCs) in constantly replenishing mammary epithelium is unclear. Here we show that DNMT1 is indispensable for MaSC maintenance. Furthermore, we find that DNMT1 expression is elevated in mammary tumours, and mammary gland-specific DNMT1 deletion protects mice from mammary tumorigenesis by limiting the CSC pool. Through genome-scale methylation studies, we identify ISL1 as a direct DNMT1 target, hypermethylated and downregulated in mammary tumours and CSCs. DNMT inhibition or ISL1 expression in breast cancer cells limits CSC population. Altogether, our studies uncover an essential role for DNMT1 in MaSC and CSC maintenance and identify DNMT1-ISL1 axis as a potential therapeutic target for breast cancer treatment.

PMID:
25908435
PMCID:
PMC4410389
DOI:
10.1038/ncomms7910
[Indexed for MEDLINE]
Free PMC Article

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