title: Remote reprogramming of hepatic circadian transcriptome by breast cancer.
abstract: Cancers adversely affect organismal physiology. To date, the genes within a patient responsible for systemically spreading cancer-induced physiological disruption remain elusive. To identify host genes responsible for transmitting disruptive, cancer-driven signals, we thoroughly analyzed the transcriptome of a suite of host organs from mice bearing 4T1 breast cancer, and discovered complexly rewired patterns of circadian gene expression in the liver. Our data revealed that 7 core clock transcription factors, represented by Rev-erba and Rorg, exhibited abnormal daily expression rhythm in the liver of 4T1-bearing mice. Accordingly, expression patterns of specific set of downstream circadian genes were compromised. Osgin1, a marker for oxidative stress, was an example. Specific downstream genes, including E2f8, a transcriptional repressor that controls cellular polyploidy, displayed a striking pattern of disruption, "day-night reversal." Meanwhile, we found that the liver of 4T1-bearing mice suffered from increased oxidative stress. The tetraploid hepatocytes population was concomitantly increased in 4T1-bearing mice, which has not been previously appreciated as a cancer-induced phenotype. In summary, the current study provides a comprehensive characterization of the 4T1-affected hepatic circadian transcriptome that possibly underlies cancer-induced physiological alteration in the liver.
authors.affiliation: Advanced Telecommunications Research Institute International (ATR), The Thomas N. Sato BioMEC-X Laboratories, Kyoto, Japan.|ERATO Sato Live Bio-Forecasting Project, Japan Science and Technology Agency (JST), Kyoto, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Hojo
authors.affiliation: Advanced Telecommunications Research Institute International (ATR), The Thomas N. Sato BioMEC-X Laboratories, Kyoto, Japan.|ERATO Sato Live Bio-Forecasting Project, Japan Science and Technology Agency (JST), Kyoto, Japan.
authors.forename: Sora
authors.initials: S
authors.lastname: Enya
authors.affiliation: Advanced Telecommunications Research Institute International (ATR), The Thomas N. Sato BioMEC-X Laboratories, Kyoto, Japan.|The University of Tokyo, Graduate School of Frontier Science, Kashiwa, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Arai
authors.affiliation: The University of Tokyo, Graduate School of Frontier Science, Kashiwa, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Suita-City, Osaka, Japan.|Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nojiri
authors.affiliation: Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Suita-City, Osaka, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kangawa
authors.affiliation: Department of Statistical Modeling, Institute of Statistical Mathematics, Tokyo, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Koyama
authors.affiliation: Advanced Telecommunications Research Institute International (ATR), The Thomas N. Sato BioMEC-X Laboratories, Kyoto, Japan.|ERATO Sato Live Bio-Forecasting Project, Japan Science and Technology Agency (JST), Kyoto, Japan.
authors.forename: Shinpei
authors.initials: S
authors.lastname: Kawaoka
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D057906:Circadian Clocks; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D051379:Mice; D009368:Neoplasm Transplantation; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics*; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics*; D018384:Oxidative Stress; D017423:Sequence Analysis, RNA / Q000379:methods*
chemical_list: C498263:Nr1d1 protein, rat; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539902:Rorc protein, rat
keywords: RNA-seq; breast cancer; hepatic circadian transcriptome; hepatic oxidative stress; hepatic polyploidization