title: Luteolin Inhibits Breast Cancer Development and Progression In Vitro and In Vivo by Suppressing Notch Signaling and Regulating MiRNAs.
abstract: OBJECTIVE
  This study aims to investigate the effect of Luteolin on breast cancer in vitro and in vivo and the interaction between miRNAs and Notch signaling after Luteolin intervention, and illustrates the possible underlying mechanism and regulation loop.
  
  
  METHODS
  Cell growth/survival assays and cell cycle analyses were performed to evaluate cell survival in vitro. Scratch tests, cell invasion assays and tube formation assays were carried out to analyze cell viability and identify the impact of Luteolin on angiogenesis. Critical components in the Notch pathway including proteins and mRNAs were detected by Western blotting analyses, ELISA assays and real-time reverse transcription-polymerase chain reaction. Matrix metalloproteinases activity was evaluated by gelatin zymography analyses. MiRNAs were analyzed by miRNA expression assays. After MDA-MB-231 cells were separately transfected with Notch-1 siRNA/cDNA and miRNA mimics, the above assays were also carried out to examine potential tumor cell changes. Xenograft models were applied to evaluate the treatment potency of Luteolin in breast cancer.
  
  
  RESULTS
  Luteolin significantly inhibited breast cancer cell survival, cell cycle, tube formation and the expression of Notch signaling-related proteins and mRNAs, and regulated miRNAs. After introducing Notch-1 siRNA and miRNA mimics, MDA-MB-231 cells presented with changes in miRNA levels, reduced Notch signaling-related proteins, and decreased tumor survival, invasion and angiogenesis.
  
  
  CONCLUSIONS
  Luteolin inhibits Notch signaling by regulating miRNAs. However, the effect of miRNAs on the Notch pathway could be either Luteolin-dependent or Luteolin-independent. Furthermore, Notch-1 alteration may inversely change miRNAs levels. Our data demonstrates that Luteolin, miRNAs and the Notch pathway are critical in breast cancer development and prognosis.
authors.forename: Da-Wei
authors.initials: DW
authors.lastname: Sun
authors.forename: He-Da
authors.initials: HD
authors.lastname: Zhang
authors.forename: Ling
authors.initials: L
authors.lastname: Mao
authors.forename: Chang-Fei
authors.initials: CF
authors.lastname: Mao
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Meng
authors.initials: M
authors.lastname: Cui
authors.forename: Rong
authors.initials: R
authors.lastname: Ma
authors.forename: Hai-Xia
authors.initials: HX
authors.lastname: Cao
authors.forename: Chang-Weng
authors.initials: CW
authors.lastname: Jing
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Wang
authors.forename: Jian-Zhong
authors.initials: JZ
authors.lastname: Wu
authors.forename: Jin-Hai
authors.initials: JH
authors.lastname: Tang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D047311:Luteolin / Q000494:pharmacology* / Q000627:therapeutic use; D061986:MCF-7 Cells; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D035683:MicroRNAs; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D042461:Vascular Endothelial Growth Factor A; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D047311:Luteolin