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GLI1 regulates a novel neuropilin-2/α6β1 integrin based autocrine pathway that contributes to breast cancer initiation

The characterization of cells with tumour initiating potential is significant for advancing our understanding of cancer and improving therapy. Aggressive, triple-negative breast cancers (TNBCs) are enriched for tumour-initiating cells (TICs). We investigated that hypothesis that VEGF receptors expre...

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Autores principales: Goel, Hira Lal, Pursell, Bryan, Chang, Cheng, Shaw, Leslie M, Mao, Junhao, Simin, Karl, Kumar, Prashant, Vander Kooi, Craig W, Shultz, Leonard D, Greiner, Dale L, Norum, Jens Henrik, Toftgard, Rune, Kuperwasser, Charlotte, Mercurio, Arthur M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: WILEY-VCH Verlag 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3628099/
https://www.ncbi.nlm.nih.gov/pubmed/23436775
http://dx.doi.org/10.1002/emmm.201202078
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author Goel, Hira Lal
Pursell, Bryan
Chang, Cheng
Shaw, Leslie M
Mao, Junhao
Simin, Karl
Kumar, Prashant
Vander Kooi, Craig W
Shultz, Leonard D
Greiner, Dale L
Norum, Jens Henrik
Toftgard, Rune
Kuperwasser, Charlotte
Mercurio, Arthur M
author_facet Goel, Hira Lal
Pursell, Bryan
Chang, Cheng
Shaw, Leslie M
Mao, Junhao
Simin, Karl
Kumar, Prashant
Vander Kooi, Craig W
Shultz, Leonard D
Greiner, Dale L
Norum, Jens Henrik
Toftgard, Rune
Kuperwasser, Charlotte
Mercurio, Arthur M
author_sort Goel, Hira Lal
collection PubMed
description The characterization of cells with tumour initiating potential is significant for advancing our understanding of cancer and improving therapy. Aggressive, triple-negative breast cancers (TNBCs) are enriched for tumour-initiating cells (TICs). We investigated that hypothesis that VEGF receptors expressed on TNBC cells mediate autocrine signalling that contributes to tumour initiation. We discovered the VEGF receptor neuropilin-2 (NRP2) is expressed preferentially on TICs, involved in the genesis of TNBCs and necessary for tumour initiation. The mechanism by which NRP2 signalling promotes tumour initiation involves stimulation of the α6β1 integrin, focal adhesion kinase-mediated activation of Ras/MEK signalling and consequent expression of the Hedgehog effector GLI1. GLI1 also induces BMI-1, a key stem cell factor, and it enhances NRP2 expression and the function of α6β1, establishing an autocrine loop. NRP2 can be targeted in vivo to retard tumour initiation. These findings reveal a novel autocrine pathway involving VEGF/NRP2, α6β1 and GLI1 that contributes to the initiation of TNBC. They also support the feasibility of NRP2-based therapy for the treatment of TNBC that targets and impedes the function of TICs.
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spelling pubmed-36280992013-04-19 GLI1 regulates a novel neuropilin-2/α6β1 integrin based autocrine pathway that contributes to breast cancer initiation Goel, Hira Lal Pursell, Bryan Chang, Cheng Shaw, Leslie M Mao, Junhao Simin, Karl Kumar, Prashant Vander Kooi, Craig W Shultz, Leonard D Greiner, Dale L Norum, Jens Henrik Toftgard, Rune Kuperwasser, Charlotte Mercurio, Arthur M EMBO Mol Med Research Article The characterization of cells with tumour initiating potential is significant for advancing our understanding of cancer and improving therapy. Aggressive, triple-negative breast cancers (TNBCs) are enriched for tumour-initiating cells (TICs). We investigated that hypothesis that VEGF receptors expressed on TNBC cells mediate autocrine signalling that contributes to tumour initiation. We discovered the VEGF receptor neuropilin-2 (NRP2) is expressed preferentially on TICs, involved in the genesis of TNBCs and necessary for tumour initiation. The mechanism by which NRP2 signalling promotes tumour initiation involves stimulation of the α6β1 integrin, focal adhesion kinase-mediated activation of Ras/MEK signalling and consequent expression of the Hedgehog effector GLI1. GLI1 also induces BMI-1, a key stem cell factor, and it enhances NRP2 expression and the function of α6β1, establishing an autocrine loop. NRP2 can be targeted in vivo to retard tumour initiation. These findings reveal a novel autocrine pathway involving VEGF/NRP2, α6β1 and GLI1 that contributes to the initiation of TNBC. They also support the feasibility of NRP2-based therapy for the treatment of TNBC that targets and impedes the function of TICs. WILEY-VCH Verlag 2013-04 2013-02-21 /pmc/articles/PMC3628099/ /pubmed/23436775 http://dx.doi.org/10.1002/emmm.201202078 Text en Copyright © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO http://creativecommons.org/licenses/by/2.5/ This is an open access article under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Goel, Hira Lal
Pursell, Bryan
Chang, Cheng
Shaw, Leslie M
Mao, Junhao
Simin, Karl
Kumar, Prashant
Vander Kooi, Craig W
Shultz, Leonard D
Greiner, Dale L
Norum, Jens Henrik
Toftgard, Rune
Kuperwasser, Charlotte
Mercurio, Arthur M
GLI1 regulates a novel neuropilin-2/α6β1 integrin based autocrine pathway that contributes to breast cancer initiation
title GLI1 regulates a novel neuropilin-2/α6β1 integrin based autocrine pathway that contributes to breast cancer initiation
title_full GLI1 regulates a novel neuropilin-2/α6β1 integrin based autocrine pathway that contributes to breast cancer initiation
title_fullStr GLI1 regulates a novel neuropilin-2/α6β1 integrin based autocrine pathway that contributes to breast cancer initiation
title_full_unstemmed GLI1 regulates a novel neuropilin-2/α6β1 integrin based autocrine pathway that contributes to breast cancer initiation
title_short GLI1 regulates a novel neuropilin-2/α6β1 integrin based autocrine pathway that contributes to breast cancer initiation
title_sort gli1 regulates a novel neuropilin-2/α6β1 integrin based autocrine pathway that contributes to breast cancer initiation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3628099/
https://www.ncbi.nlm.nih.gov/pubmed/23436775
http://dx.doi.org/10.1002/emmm.201202078
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