title: Haploinsufficiency for BRCA1 leads to cell-type-specific genomic instability and premature senescence.
abstract: Although BRCA1 function is essential for maintaining genomic integrity in all cell types, it is unclear why increased risk of cancer in individuals harbouring deleterious mutations in BRCA1 is restricted to only a select few tissues. Here we show that human mammary epithelial cells (HMECs) from BRCA1-mutation carriers (BRCA1(mut/+)) exhibit increased genomic instability and rapid telomere erosion in the absence of tumour-suppressor loss. Furthermore, we uncover a novel form of haploinsufficiency-induced senescence (HIS) specific to epithelial cells, which is triggered by pRb pathway activation rather than p53 induction. HIS and telomere erosion in HMECs correlate with misregulation of SIRT1 leading to increased levels of acetylated pRb as well as acetylated H4K16 both globally and at telomeric regions. These results identify a novel form of cellular senescence and provide a potential molecular basis for the rapid cell- and tissue- specific predisposition of breast cancer development associated with BRCA1 haploinsufficiency.
authors.affiliation: 1] Program in Cell, Molecular and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Avenue, Boston, Massachusetts 02111, USA [2] Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, Massachusetts 02111, USA.
authors.forename: Maja
authors.initials: M
authors.lastname: Sedic
authors.affiliation: 1] Program in Cell, Molecular and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Avenue, Boston, Massachusetts 02111, USA [2] Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, Massachusetts 02111, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Skibinski
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, Massachusetts 02111, USA.
authors.forename: Nelson
authors.initials: N
authors.lastname: Brown
authors.affiliation: Telomeres and Telomerase Group, Spanish National Cancer Centre, Madrid E-28029, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Gallardo
authors.affiliation: Department of Cell Biology, Harvard Medical School and Massachusetts General Hospital Cancer Center, Building 149, 13th Street, Charlestown, Massachusetts 02129, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Mulligan
authors.affiliation: Telomeres and Telomerase Group, Spanish National Cancer Centre, Madrid E-28029, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Martinez
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, Massachusetts 02111, USA.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Keller
authors.affiliation: 1] Program in Cell, Molecular and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Avenue, Boston, Massachusetts 02111, USA [2] Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, Massachusetts 02111, USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Glover
authors.affiliation: Department of Pathology, Harvard Medical School, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Richardson
authors.affiliation: Department of Pathology, Tufts Medical Center, 800 Washington Street, Boston, Massachusetts 02111, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Cowan
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, Department of Internal Medicine's Division of Human Genetics, Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Amanda E
authors.initials: AE
authors.lastname: Toland
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, 36th and Spruce Sts. Philadelphia, Pennsylvania 19104, USA.
authors.forename: Krithika
authors.initials: K
authors.lastname: Ravichandran
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, 36th and Spruce Sts. Philadelphia, Pennsylvania 19104, USA.
authors.forename: Harold
authors.initials: H
authors.lastname: Riethman
authors.affiliation: Department of Pathology, Tufts Medical Center, 800 Washington Street, Boston, Massachusetts 02111, USA.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Naber
authors.affiliation: Department of Cell Biology, Harvard Medical School and Massachusetts General Hospital Cancer Center, Building 149, 13th Street, Charlestown, Massachusetts 02129, USA.
authors.forename: Anders M
authors.initials: AM
authors.lastname: Näär
authors.affiliation: Telomeres and Telomerase Group, Spanish National Cancer Centre, Madrid E-28029, Spain.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Blasco
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, Massachusetts 02111, USA.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Hinds
authors.affiliation: 1] Program in Cell, Molecular and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Avenue, Boston, Massachusetts 02111, USA [2] Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, Massachusetts 02111, USA.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Kuperwasser
mesh_terms: D016922:Cellular Senescence / Q000235:genetics*; D004249:DNA Damage; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D019398:Genes, BRCA1; D042822:Genomic Instability / Q000235:genetics*; D057895:Haploinsufficiency; D006579:Heterozygote; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology / Q000378:metabolism*; D009154:Mutation; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D059506:Telomere Shortening / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D016160:Retinoblastoma Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C447939:SIRT1 protein, human; D056564:Sirtuin 1