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

doi:10.1038/ncb3058

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

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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 language	English
Pages (from-to)	1238-1248
Number of pages	11
Journal	Nature Cell Biology
Volume	16
Issue number	12
DOIs	https://doi.org/10.1038/ncb3058
State	Published - 1 Dec 2014

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Scheeren, F. A., Kuo, A. H., Van Weele, L. J., Cai, S., Glykofridis, I., Sikandar, S. S., Zabala, M., Qian, D., Lam, J. S., Johnston, D., Volkmer, J. P., Sahoo, D., Van De Rijn, M., Dirbas, F. M., Somlo, G., Kalisky, T., Rothenberg, M. E., Quake, S. R., & Clarke, M. F. (2014). A cell-intrinsic role for TLR2-MYD88 in intestinal and breast epithelia and oncogenesis. Nature Cell Biology, 16(12), 1238-1248. https://doi.org/10.1038/ncb3058

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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.",

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

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Scheeren, FA, Kuo, AH, Van Weele, LJ, Cai, S, Glykofridis, I, Sikandar, SS, Zabala, M, Qian, D, Lam, JS, Johnston, D, Volkmer, JP, Sahoo, D, Van De Rijn, M, Dirbas, FM, Somlo, G, Kalisky, T, Rothenberg, ME, Quake, SR & Clarke, MF 2014, 'A cell-intrinsic role for TLR2-MYD88 in intestinal and breast epithelia and oncogenesis', Nature Cell Biology, vol. 16, no. 12, pp. 1238-1248. https://doi.org/10.1038/ncb3058

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AU - Scheeren, Ferenc A.

AU - Kuo, Angera H.

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AU - Cai, Shang

AU - Glykofridis, Iris

AU - Sikandar, Shaheen S.

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AU - Johnston, Darius

AU - Volkmer, Jens P.

AU - Sahoo, Debashis

AU - Van De Rijn, Matt

AU - Dirbas, Frederick M.

AU - Somlo, George

AU - Kalisky, Tomer

AU - Rothenberg, Michael E.

AU - Quake, Stephen R.

AU - Clarke, Michael F.

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

Abstract

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