A cell-intrinsic role for TLR2-MYD88 in intestinal and breast epithelia and oncogenesis

Ferenc A. Scheeren, Angera H. Kuo, Linda J. Van Weele, Shang Cai, Iris Glykofridis, Shaheen S. Sikandar, Maider Zabala, Dalong Qian, Jessica S. Lam, Darius Johnston, Jens P. Volkmer, Debashis Sahoo, Matt Van De Rijn, Frederick M. Dirbas, George Somlo, Tomer Kalisky, Michael E. Rothenberg, Stephen R. Quake, Michael F. Clarke

Research output: Contribution to journalArticlepeer-review

95 Scopus citations

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.

Original languageEnglish
Pages (from-to)1238-1248
Number of pages11
JournalNature Cell Biology
Volume16
Issue number12
DOIs
StatePublished - 1 Dec 2014

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