title: Gut bacteria require neutrophils to promote mammary tumorigenesis.
abstract: Recent studies suggest that gastrointestinal tract microbiota modulate cancer development in distant non-intestinal tissues. Here we tested mechanistic hypotheses using a targeted pathogenic gut microbial infection animal model with a predilection to breast cancer. FVB-Tg(C3-1-TAg)cJeg/JegJ female mice were infected by gastric gavage with Helicobacter hepaticus at three-months-of-age putting them at increased risk for mammary tumor development. Tumorigenesis was multifocal and characterized by extensive infiltrates of myeloperoxidase-positive neutrophils otherwise implicated in cancer progression in humans and animal models. To test whether neutrophils were important in etiopathogenesis in this bacteria-triggered model system, we next systemically depleted mice of neutrophils using thrice weekly intraperitoneal injections with anti-Ly-6G antibody. We found that antibody depletion entirely inhibited tumor development in this H. hepaticus-infected model. These data demonstrate that host neutrophil-associated immune responses to intestinal tract microbes significantly impact cancer progression in distal tissues such as mammary glands, and identify gut microbes as novel targets for extra-intestinal cancer therapy.
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Lakritz
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.|Laboratory of Pathology, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, Greece 54124.
authors.forename: Theofilos
authors.initials: T
authors.lastname: Poutahidis
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Sheyla
authors.initials: S
authors.lastname: Mirabal
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: Varian
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Levkovich
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Yassin M
authors.initials: YM
authors.lastname: Ibrahim
authors.affiliation: Global VetPathology, Montgomery Village, MD 20886, USA.
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Ward
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Teng
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Brett
authors.initials: B
authors.lastname: Fisher
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Parry
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Lesage
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Alberg
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Sravya
authors.initials: S
authors.lastname: Gourishetti
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Fox
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Ge
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Erdman
mesh_terms: D000818:Animals; D001419:Bacteria / Q000276:immunology*; D063646:Carcinogenesis / Q000276:immunology*; D005260:Female; D016481:Helicobacter Infections / Q000276:immunology; D044923:Helicobacter hepaticus / Q000276:immunology; D007422:Intestines / Q000276:immunology / Q000382:microbiology*; D015674:Mammary Neoplasms, Animal / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D064307:Microbiota / Q000276:immunology / Q000502:physiology*; D009504:Neutrophils / Q000473:pathology / Q000502:physiology*
keywords: bacteria; enteric; immune system; mammary cancer; microbes
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