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The LPA1/ZEB1/miR-21-activation pathway regulates metastasis in basal breast cancer

Lysophosphatidic acid (LPA) is a bioactive lipid promoting cancer metastasis. LPA activates a series of six G protein-coupled receptors (LPA(1-6)). While blockage of LPA(1) in vivo inhibits breast carcinoma metastasis, down-stream genes mediating LPA-induced metastasis have not been yet identified....

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Autores principales: Sahay, Debashish, Leblanc, Raphael, Grunewald, Thomas G. P., Ambatipudi, Srikant, Ribeiro, Johnny, Clézardin, Philippe, Peyruchaud, Olivier
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4653029/
https://www.ncbi.nlm.nih.gov/pubmed/26098771
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author Sahay, Debashish
Leblanc, Raphael
Grunewald, Thomas G. P.
Ambatipudi, Srikant
Ribeiro, Johnny
Clézardin, Philippe
Peyruchaud, Olivier
author_facet Sahay, Debashish
Leblanc, Raphael
Grunewald, Thomas G. P.
Ambatipudi, Srikant
Ribeiro, Johnny
Clézardin, Philippe
Peyruchaud, Olivier
author_sort Sahay, Debashish
collection PubMed
description Lysophosphatidic acid (LPA) is a bioactive lipid promoting cancer metastasis. LPA activates a series of six G protein-coupled receptors (LPA(1-6)). While blockage of LPA(1) in vivo inhibits breast carcinoma metastasis, down-stream genes mediating LPA-induced metastasis have not been yet identified. Herein we showed by analyzing publicly available expression data from 1488 human primary breast tumors that the gene encoding the transcription factor ZEB1 was the most correlated with LPAR1 encoding LPA(1). This correlation was most prominent in basal primary breast carcinomas and restricted to cell lines of basal subtypes. Functional experiments in three different basal cell lines revealed that LPA-induced ZEB1 expression was regulated by the LPA(1)/Phosphatidylinositol-3-Kinase (Pi3K) axis. DNA microarray and real-time PCR analyses further demonstrated that LPA up-regulated the oncomiR miR-21 through an LPA(1)/Pi3K/ZEB1-dependent mechanism. Strikingly, treatment with a mirVana miR-21 inhibitor, or silencing LPA(1) or ZEB1 completely blocked LPA-induced cell migration in vitro, invasion and tumor cell bone colonization in vivo, which can be restored with a mirVana miR-21 mimic. Finally, high LPAR1 expression in basal breast tumors predicted worse lung-metastasis-free survival. Collectively, our results elucidate a new molecular pathway driving LPA-induced metastasis, thus underscoring the therapeutic potential of targeting LPA(1) in patients with basal breast carcinomas.
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spelling pubmed-46530292015-12-02 The LPA1/ZEB1/miR-21-activation pathway regulates metastasis in basal breast cancer Sahay, Debashish Leblanc, Raphael Grunewald, Thomas G. P. Ambatipudi, Srikant Ribeiro, Johnny Clézardin, Philippe Peyruchaud, Olivier Oncotarget Research Paper Lysophosphatidic acid (LPA) is a bioactive lipid promoting cancer metastasis. LPA activates a series of six G protein-coupled receptors (LPA(1-6)). While blockage of LPA(1) in vivo inhibits breast carcinoma metastasis, down-stream genes mediating LPA-induced metastasis have not been yet identified. Herein we showed by analyzing publicly available expression data from 1488 human primary breast tumors that the gene encoding the transcription factor ZEB1 was the most correlated with LPAR1 encoding LPA(1). This correlation was most prominent in basal primary breast carcinomas and restricted to cell lines of basal subtypes. Functional experiments in three different basal cell lines revealed that LPA-induced ZEB1 expression was regulated by the LPA(1)/Phosphatidylinositol-3-Kinase (Pi3K) axis. DNA microarray and real-time PCR analyses further demonstrated that LPA up-regulated the oncomiR miR-21 through an LPA(1)/Pi3K/ZEB1-dependent mechanism. Strikingly, treatment with a mirVana miR-21 inhibitor, or silencing LPA(1) or ZEB1 completely blocked LPA-induced cell migration in vitro, invasion and tumor cell bone colonization in vivo, which can be restored with a mirVana miR-21 mimic. Finally, high LPAR1 expression in basal breast tumors predicted worse lung-metastasis-free survival. Collectively, our results elucidate a new molecular pathway driving LPA-induced metastasis, thus underscoring the therapeutic potential of targeting LPA(1) in patients with basal breast carcinomas. Impact Journals LLC 2015-04-27 /pmc/articles/PMC4653029/ /pubmed/26098771 Text en Copyright: © 2015 Sahay et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Sahay, Debashish
Leblanc, Raphael
Grunewald, Thomas G. P.
Ambatipudi, Srikant
Ribeiro, Johnny
Clézardin, Philippe
Peyruchaud, Olivier
The LPA1/ZEB1/miR-21-activation pathway regulates metastasis in basal breast cancer
title The LPA1/ZEB1/miR-21-activation pathway regulates metastasis in basal breast cancer
title_full The LPA1/ZEB1/miR-21-activation pathway regulates metastasis in basal breast cancer
title_fullStr The LPA1/ZEB1/miR-21-activation pathway regulates metastasis in basal breast cancer
title_full_unstemmed The LPA1/ZEB1/miR-21-activation pathway regulates metastasis in basal breast cancer
title_short The LPA1/ZEB1/miR-21-activation pathway regulates metastasis in basal breast cancer
title_sort lpa1/zeb1/mir-21-activation pathway regulates metastasis in basal breast cancer
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4653029/
https://www.ncbi.nlm.nih.gov/pubmed/26098771
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