title: DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.
authors.forename: Rajneesh
authors.initials: R
authors.lastname: Pathania
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.
authors.forename: Sabarish
authors.initials: S
authors.lastname: Ramachandran
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.
authors.forename: Selvakumar
authors.initials: S
authors.lastname: Elangovan
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Padia
authors.affiliation: 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.
authors.forename: Pengyi
authors.initials: P
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Senthilkumar
authors.initials: S
authors.lastname: Cinghu
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.
authors.forename: Rajalakshmi
authors.initials: R
authors.lastname: Veeranan-Karmegam
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.
authors.forename: Pachiappan
authors.initials: P
authors.lastname: Arjunan
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.
authors.forename: Jaya P
authors.initials: JP
authors.lastname: Gnana-Prakasam
authors.affiliation: Department of Orthopedic Surgery, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.
authors.forename: Fulzele
authors.initials: F
authors.lastname: Sadanand
authors.affiliation: Department of Pathology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.
authors.forename: Lirong
authors.initials: L
authors.lastname: Pei
authors.affiliation: Department of Pathology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.
authors.forename: Chang-Sheng
authors.initials: CS
authors.lastname: Chang
authors.affiliation: Department of Biostatistics, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.|Cancer Research Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.
authors.forename: Jeong-Hyeon
authors.initials: JH
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.|Cancer Research Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.
authors.forename: Huidong
authors.initials: H
authors.lastname: Shi
authors.affiliation: Cancer Research Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.
authors.forename: Santhakumar
authors.initials: S
authors.lastname: Manicassamy
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.|Cancer Research Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.
authors.forename: Puttur D
authors.initials: PD
authors.lastname: Prasad
authors.affiliation: Department of Pathology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.|Cancer Research Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.
authors.forename: Suash
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.|Cancer Research Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.
authors.forename: Vadivel
authors.initials: V
authors.lastname: Ganapathy
authors.affiliation: 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.
authors.forename: Raja
authors.initials: R
authors.lastname: Jothi
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.|Cancer Research Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Thangaraju
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D015536:Down-Regulation; D005260:Female; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D061986:MCF-7 Cells; D008321:Mammary Glands, Animal / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse