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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antigens, Neoplasm / metabolism
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Breast / metabolism
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Breast / pathology*
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Breast Neoplasms / genetics
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Breast Neoplasms / pathology*
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Carcinogenesis / genetics
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Carcinogenesis / metabolism*
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Cell Adhesion Molecules / metabolism
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Colitis / chemically induced
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Colitis / pathology
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Colonic Neoplasms / genetics
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Colonic Neoplasms / pathology*
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Dextran Sulfate
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Epithelial Cell Adhesion Molecule
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Epithelium / pathology
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Female
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HEK293 Cells
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Humans
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Interleukin-1 Receptor-Associated Kinases / antagonists & inhibitors
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Interleukin-1 Receptor-Associated Kinases / genetics
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Intestinal Mucosa / metabolism
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Intestinal Mucosa / pathology*
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Leukocyte Common Antigens / genetics
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Lipopolysaccharide Receptors / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Myeloid Differentiation Factor 88 / antagonists & inhibitors
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Myeloid Differentiation Factor 88 / genetics
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Myeloid Differentiation Factor 88 / metabolism*
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Neoplasm Transplantation
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RNA Interference
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RNA, Small Interfering
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Receptors, G-Protein-Coupled / metabolism
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Regeneration / genetics
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Signal Transduction
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Toll-Like Receptor 2 / antagonists & inhibitors
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Toll-Like Receptor 2 / genetics
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Toll-Like Receptor 2 / metabolism*
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Tumor Cells, Cultured
Substances
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Antigens, Neoplasm
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Cell Adhesion Molecules
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Epithelial Cell Adhesion Molecule
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Lgr5 protein, mouse
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Lipopolysaccharide Receptors
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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RNA, Small Interfering
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Receptors, G-Protein-Coupled
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Tlr2 protein, mouse
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Toll-Like Receptor 2
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Dextran Sulfate
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IRAK1 protein, human
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IRAK4 protein, human
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Interleukin-1 Receptor-Associated Kinases
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Leukocyte Common Antigens
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Ptprc protein, mouse