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Loss of ABAT-Mediated GABAergic System Promotes Basal-Like Breast Cancer Progression by Activating Ca(2+)-NFAT1 Axis
Basal-like breast cancer (BLBC) is the most aggressive subtype with a poor clinical outcome; however, the molecular mechanisms underlying aggressiveness in BLBC remain poorly understood. Methods: The effects of gamma-aminobutyrate aminotransferase (ABAT) on GABA receptors, Ca(2+)-NFAT1 axis, and can...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332792/ https://www.ncbi.nlm.nih.gov/pubmed/30662552 http://dx.doi.org/10.7150/thno.29407 |
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author | Chen, Xingyu Cao, Qianhua Liao, Ruocen Wu, Xuebiao Xun, Shining Huang, Jian Dong, Chenfang |
author_facet | Chen, Xingyu Cao, Qianhua Liao, Ruocen Wu, Xuebiao Xun, Shining Huang, Jian Dong, Chenfang |
author_sort | Chen, Xingyu |
collection | PubMed |
description | Basal-like breast cancer (BLBC) is the most aggressive subtype with a poor clinical outcome; however, the molecular mechanisms underlying aggressiveness in BLBC remain poorly understood. Methods: The effects of gamma-aminobutyrate aminotransferase (ABAT) on GABA receptors, Ca(2+)-NFAT1 axis, and cancer cell behavior were assessed by Ca(2+) imaging, Western blotting, immunostaining, colony formation, and migration and invasion assays. We elucidated the relationship between ABAT and Snail by luciferase reporter and ChIP assays. The effect of ABAT expression on BLBC cells was determined by in vitro and in vivo tumorigenesis and a lung metastasis mouse model. Results: We showed that, compared to other subtypes, ABAT was considerably decreased in BLBC. Mechanistically, ABAT expression was downregulated due to Snail-mediated repression leading to increased GABA production. GABA then elevated intracellular Ca(2+) concentration by activating GABA-A receptor (GABA(A)), which contributed to the efficient activation of NFAT1 in BLBC cells. ABAT expression resulted in inhibition of tumorigenicity, both in vitro and in vivo, and metastasis of BLBC cells. Thus, loss of ABAT contributed to BLBC aggressiveness by activating the Ca(2+)-NFAT1 axis. In breast cancer patients, loss of ABAT expression was strongly correlated with large tumor size, high grade and metastatic tendency, poor survival, and chemotherapy resistance. Conclusions: Our findings have provided underlying molecular details for the aggressive behavior of BLBC. The Snail-mediated downregulation of ABAT expression in BLBC provides tumorigenic and metastatic advantages by activating GABA-mediated Ca(2+)-NFAT1 axis. Thus, our results have identified potential prognostic indicators and therapeutic targets for this challenging disease. |
format | Online Article Text |
id | pubmed-6332792 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
spelling | pubmed-63327922019-01-18 Loss of ABAT-Mediated GABAergic System Promotes Basal-Like Breast Cancer Progression by Activating Ca(2+)-NFAT1 Axis Chen, Xingyu Cao, Qianhua Liao, Ruocen Wu, Xuebiao Xun, Shining Huang, Jian Dong, Chenfang Theranostics Research Paper Basal-like breast cancer (BLBC) is the most aggressive subtype with a poor clinical outcome; however, the molecular mechanisms underlying aggressiveness in BLBC remain poorly understood. Methods: The effects of gamma-aminobutyrate aminotransferase (ABAT) on GABA receptors, Ca(2+)-NFAT1 axis, and cancer cell behavior were assessed by Ca(2+) imaging, Western blotting, immunostaining, colony formation, and migration and invasion assays. We elucidated the relationship between ABAT and Snail by luciferase reporter and ChIP assays. The effect of ABAT expression on BLBC cells was determined by in vitro and in vivo tumorigenesis and a lung metastasis mouse model. Results: We showed that, compared to other subtypes, ABAT was considerably decreased in BLBC. Mechanistically, ABAT expression was downregulated due to Snail-mediated repression leading to increased GABA production. GABA then elevated intracellular Ca(2+) concentration by activating GABA-A receptor (GABA(A)), which contributed to the efficient activation of NFAT1 in BLBC cells. ABAT expression resulted in inhibition of tumorigenicity, both in vitro and in vivo, and metastasis of BLBC cells. Thus, loss of ABAT contributed to BLBC aggressiveness by activating the Ca(2+)-NFAT1 axis. In breast cancer patients, loss of ABAT expression was strongly correlated with large tumor size, high grade and metastatic tendency, poor survival, and chemotherapy resistance. Conclusions: Our findings have provided underlying molecular details for the aggressive behavior of BLBC. The Snail-mediated downregulation of ABAT expression in BLBC provides tumorigenic and metastatic advantages by activating GABA-mediated Ca(2+)-NFAT1 axis. Thus, our results have identified potential prognostic indicators and therapeutic targets for this challenging disease. Ivyspring International Publisher 2019-01-01 /pmc/articles/PMC6332792/ /pubmed/30662552 http://dx.doi.org/10.7150/thno.29407 Text en © Ivyspring International Publisher This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions. |
spellingShingle | Research Paper Chen, Xingyu Cao, Qianhua Liao, Ruocen Wu, Xuebiao Xun, Shining Huang, Jian Dong, Chenfang Loss of ABAT-Mediated GABAergic System Promotes Basal-Like Breast Cancer Progression by Activating Ca(2+)-NFAT1 Axis |
title | Loss of ABAT-Mediated GABAergic System Promotes Basal-Like Breast Cancer Progression by Activating Ca(2+)-NFAT1 Axis |
title_full | Loss of ABAT-Mediated GABAergic System Promotes Basal-Like Breast Cancer Progression by Activating Ca(2+)-NFAT1 Axis |
title_fullStr | Loss of ABAT-Mediated GABAergic System Promotes Basal-Like Breast Cancer Progression by Activating Ca(2+)-NFAT1 Axis |
title_full_unstemmed | Loss of ABAT-Mediated GABAergic System Promotes Basal-Like Breast Cancer Progression by Activating Ca(2+)-NFAT1 Axis |
title_short | Loss of ABAT-Mediated GABAergic System Promotes Basal-Like Breast Cancer Progression by Activating Ca(2+)-NFAT1 Axis |
title_sort | loss of abat-mediated gabaergic system promotes basal-like breast cancer progression by activating ca(2+)-nfat1 axis |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332792/ https://www.ncbi.nlm.nih.gov/pubmed/30662552 http://dx.doi.org/10.7150/thno.29407 |
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