title: Role of STAT5 and epigenetics in lactation-associated upregulation of multidrug transporter ABCG2 in the mammary gland.
abstract: The multidrug resistance efflux transporter ATP-binding cassette subfamily G member 2 (ABCG2) is not only overexpressed in certain drug-resistant cancers but is also highly expressed in the mammary gland during lactation, carrying xenobiotics and nutrients into milk. We sought to investigate the molecular mechanisms involved in the upregulation of ABCG2 during lactation. Expression profiling of different mouse Abcg2 mRNA isoforms (E1a, E1b, and E1c) revealed that E1b is predominantly expressed and induced in the lactating mouse mammary gland. Despite this induction, analyses of CpG methylation status and published ChIP-seq datasets reveal that E1b promoter sequences in the virgin gland are already hypomethylated and marked with the open chromatin histone mark H3K4me2. Using a forced-weaning model to shut down lactation, we found that within 24 h there was a significant reduction in Abcg2 mRNA expression and a loss of signal transducer and activator of transcription-5 (STAT5) occupancy at the mouse Abcg2 gene. Luciferase reporter assays further showed that some of these STAT5-binding regions that contained interferon-γ-activated sequence (GAS) motifs function as an enhancer after prolactin treatment. We conclude that Abcg2 is already poised for expression in the virgin mammary gland and that STAT5 plays an important role in Abcg2 expression during lactation.
authors.affiliation: Physiology and Experimental Medicine Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada;
authors.forename: Alex Man Lai
authors.initials: AM
authors.lastname: Wu
authors.affiliation: Physiology and Experimental Medicine Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada;
authors.forename: Mingdong
authors.initials: M
authors.lastname: Yang
authors.affiliation: Physiology and Experimental Medicine Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada;
authors.forename: Pooja
authors.initials: P
authors.lastname: Dalvi
authors.affiliation: Centre for Computational Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada;
authors.forename: Andrei L
authors.initials: AL
authors.lastname: Turinsky
authors.affiliation: Developmental and Stem Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada;
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada;
authors.forename: Darci
authors.initials: D
authors.lastname: Butcher
authors.affiliation: Developmental and Stem Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada;
authors.forename: Sean E
authors.initials: SE
authors.lastname: Egan
authors.affiliation: Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada; and Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Weksberg
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada;
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Harper
authors.affiliation: Physiology and Experimental Medicine Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada; Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada; and shinya.ito@sickkids.ca.
authors.forename: Shinya
authors.initials: S
authors.lastname: Ito
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D007774:Lactation / Q000235:genetics*; D008321:Mammary Glands, Animal / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D011401:Promoter Regions, Genetic; D059368:RNA Isoforms / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D050799:STAT5 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D059368:RNA Isoforms; D012333:RNA, Messenger; D050799:STAT5 Transcription Factor
keywords: ABCG2; STAT5; drug transporter; epigenetics; lactation; prolactin