title: Role of a polyphenol-enriched preparation on chemoprevention of mammary carcinoma through cancer stem cells and inflammatory pathways modulation.
abstract: BACKGROUND
  Naturally occurring polyphenolic compounds from fruits, particularly from blueberries, have been reported to be significantly involved in cancer chemoprevention and chemotherapy. Biotransformation of blueberry juice by Serratia vaccinii increases its polyphenolic content and endows it with anti-inflammatory properties.
  
  
  METHODS
  This study evaluated the effect of a polyphenol-enriched blueberry preparation (PEBP) and its non-fermented counterpart (NBJ), on mammary cancer stem cell (CSC) development in in vitro, in vivo and ex vivo settings. Effects of PEBP on cell proliferation, mobility, invasion, and mammosphere formation were measured in vitro in three cell lines: murine 4T1 and human MCF7 and MDA-MB-231. Ex vivo mammosphere formation, tumor growth and metastasis observations were carried out in a BALB/c mouse model.
  
  
  RESULTS
  Our research revealed that PEBP influence cellular signaling cascades of breast CSCs, regulating the activity of transcription factors and, consequently, inhibiting tumor growth in vivo by decreasing metastasis and controlling PI3K/AKT, MAPK/ERK, and STAT3 pathways, central nodes in CSC inflammatory signaling. PEBP significantly inhibited cell proliferation of 4T1, MCF-7 and MDA-MB-231. In all cell lines, PEBP reduced mammosphere formation, cell mobility and cell migration. In vivo, PEBP significantly reduced tumor development, inhibited the formation of ex vivo mammospheres, and significantly reduced lung metastasis.
  
  
  CONCLUSIONS
  This study showed that polyphenol enrichment of a blueberry preparation by fermentation increases its chemopreventive potential by protecting mice against tumor development, inhibiting the formation of cancer stem cells and reducing lung metastasis. Thus, PEBP may represent a novel complementary alternative medicine therapy and a source for novel therapeutic agents against breast cancer.
authors.affiliation: Nutritional Sciences Program, Faculty of Health Sciences, University of Ottawa, R2057 Roger Guindon Hall, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada. vuongptri@yahoo.ca.
authors.forename: Tri
authors.initials: T
authors.lastname: Vuong
authors.affiliation: Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Canada. jmallet@uottawa.ca.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Mallet
authors.affiliation: Cancer Center, Georgia Regents University, Augusta, GA, USA. mouzounova@gru.edu.
authors.forename: Maria
authors.initials: M
authors.lastname: Ouzounova
authors.affiliation: Nutritional Sciences Program, Faculty of Health Sciences, University of Ottawa, R2057 Roger Guindon Hall, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada. srahb089@uottawa.ca.
authors.forename: Sam
authors.initials: S
authors.lastname: Rahbar
authors.affiliation: International Agency for Research on Cancer, Lyon, France. vargash@iarc.fr.
authors.forename: Hector
authors.initials: H
authors.lastname: Hernandez-Vargas
authors.affiliation: International Agency for Research on Cancer, Lyon, France. herceg@iarc.fr.
authors.forename: Zdenko
authors.initials: Z
authors.lastname: Herceg
authors.affiliation: Nutritional Sciences Program, Faculty of Health Sciences, University of Ottawa, R2057 Roger Guindon Hall, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada. chantal.matar@uottawa.ca.
authors.forename: Chantal
authors.initials: C
authors.lastname: Matar
mesh_terms: D000818:Animals; D029798:Blueberry Plants / Q000737:chemistry; D001943:Breast Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018890:Chemoprevention; D004195:Disease Models, Animal; D005260:Female; D005285:Fermentation; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use; D059808:Polyphenols / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology
chemical_list: D010936:Plant Extracts; D059808:Polyphenols; D020928:Mitogen-Activated Protein Kinases