title: A cell-intrinsic role for TLR2-MYD88 in intestinal and breast epithelia and oncogenesis.
abstract: It has been postulated that there is a link between inflammation and cancer. Here we describe a role for cell-intrinsic toll-like receptor-2 (TLR2; which is involved in inflammatory response) signalling in normal intestinal and mammary epithelial cells and oncogenesis. The downstream effectors of TLR2 are expressed by normal intestinal and mammary epithelia, including the stem/progenitor cells. Deletion of MYD88 or TLR2 in the intestinal epithelium markedly reduces DSS-induced colitis regeneration and spontaneous tumour development in mice. Limiting dilution transplantations of breast epithelial cells devoid of TLR2 or MYD88 revealed a significant decrease in mammary repopulating unit frequency compared with the control. Inhibition of TLR2, its co-receptor CD14, or its downstream targets MYD88 and IRAK1 inhibits growth of human breast cancers in vitro and in vivo. These results suggest that inhibitors of the TLR2 pathway merit investigation as possible therapeutic and chemoprevention agents.
authors.affiliation: 1] Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, 265 Campus Drive Stanford, California 94305, USA [2] The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: Ferenc A
authors.initials: FA
authors.lastname: Scheeren
authors.affiliation: Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, 265 Campus Drive Stanford, California 94305, USA.
authors.forename: Angera H
authors.initials: AH
authors.lastname: Kuo
authors.affiliation: Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, 265 Campus Drive Stanford, California 94305, USA.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: van Weele
authors.affiliation: Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, 265 Campus Drive Stanford, California 94305, USA.
authors.forename: Shang
authors.initials: S
authors.lastname: Cai
authors.affiliation: The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: Iris
authors.initials: I
authors.lastname: Glykofridis
authors.affiliation: Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, 265 Campus Drive Stanford, California 94305, USA.
authors.forename: Shaheen S
authors.initials: SS
authors.lastname: Sikandar
authors.affiliation: Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, 265 Campus Drive Stanford, California 94305, USA.
authors.forename: Maider
authors.initials: M
authors.lastname: Zabala
authors.affiliation: Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, 265 Campus Drive Stanford, California 94305, USA.
authors.forename: Dalong
authors.initials: D
authors.lastname: Qian
authors.affiliation: Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, 265 Campus Drive Stanford, California 94305, USA.
authors.forename: Jessica S
authors.initials: JS
authors.lastname: Lam
authors.affiliation: Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, 265 Campus Drive Stanford, California 94305, USA.
authors.forename: Darius
authors.initials: D
authors.lastname: Johnston
authors.affiliation: Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, 265 Campus Drive Stanford, California 94305, USA.
authors.forename: Jens P
authors.initials: JP
authors.lastname: Volkmer
authors.affiliation: Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, 265 Campus Drive Stanford, California 94305, USA.
authors.forename: Debashis
authors.initials: D
authors.lastname: Sahoo
authors.affiliation: Department of Pathology, Stanford University, Stanford, California 94305, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: van de Rijn
authors.affiliation: Department of Surgery, Stanford University, Stanford, California 94305, USA.
authors.forename: Frederick M
authors.initials: FM
authors.lastname: Dirbas
authors.affiliation: Department of Medical Oncology, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, California 91010, USA.
authors.forename: George
authors.initials: G
authors.lastname: Somlo
authors.affiliation: Department of Bioengineering and Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA.
authors.forename: Tomer
authors.initials: T
authors.lastname: Kalisky
authors.affiliation: Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, 265 Campus Drive Stanford, California 94305, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Rothenberg
authors.affiliation: Department of Bioengineering and Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Quake
authors.affiliation: 1] Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, 265 Campus Drive Stanford, California 94305, USA [2] Department of medicine, Division of Oncology, Stanford University, Stanford, California 94305, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Clarke
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D001940:Breast / Q000378:metabolism / Q000473:pathology*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology*; D016264:Dextran Sulfate; D000071858:Epithelial Cell Adhesion Molecule; D004848:Epithelium / Q000473:pathology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology*; D017493:Leukocyte Common Antigens / Q000235:genetics; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D034622:RNA Interference; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D012038:Regeneration / Q000235:genetics; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; C493597:Lgr5 protein, mouse; D018950:Lipopolysaccharide Receptors; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D016264:Dextran Sulfate; C507768:IRAK1 protein, human; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse