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Fascin is involved in the chemotherapeutic resistance of breast cancer cells predominantly via the PI3K/Akt pathway

BACKGROUND: A major therapeutic challenge for breast cancer is the ability of cancer cells to evade killing of conventional chemotherapeutic agents. We have recently reported the actin-bundling protein (fascin) as a major regulator of breast cancer metastasis and survival. METHODS: Survival of breas...

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Autores principales: Ghebeh, H, Al-Khaldi, S, Olabi, S, Al-Dhfyan, A, Al-Mohanna, F, Barnawi, R, Tulbah, A, Al-Tweigeri, T, Ajarim, D, Al-Alwan, M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200093/
https://www.ncbi.nlm.nih.gov/pubmed/25117814
http://dx.doi.org/10.1038/bjc.2014.453
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author Ghebeh, H
Al-Khaldi, S
Olabi, S
Al-Dhfyan, A
Al-Mohanna, F
Barnawi, R
Tulbah, A
Al-Tweigeri, T
Ajarim, D
Al-Alwan, M
author_facet Ghebeh, H
Al-Khaldi, S
Olabi, S
Al-Dhfyan, A
Al-Mohanna, F
Barnawi, R
Tulbah, A
Al-Tweigeri, T
Ajarim, D
Al-Alwan, M
author_sort Ghebeh, H
collection PubMed
description BACKGROUND: A major therapeutic challenge for breast cancer is the ability of cancer cells to evade killing of conventional chemotherapeutic agents. We have recently reported the actin-bundling protein (fascin) as a major regulator of breast cancer metastasis and survival. METHODS: Survival of breast cancer patients that received chemotherapy and xenograft tumour model was used to assess the effect of chemotherapy on fascin-positive and -negative breast cancer cells. Molecular and cellular assays were used to gain in-depth understanding of the relationship between fascin and chemoresistance. RESULTS: We showed a significant correlation between fascin expression and shorter survival in breast cancer patients who received chemotherapy. In xenograft experiments, fascin-positive cancer cells displayed significantly more resistance to chemotherapy-mediated apoptotic cell death than fascin-negative counterparts. This increased chemoresistance was at least partially mediated through PI3K/Akt signalling, and was paralleled by increased FAK phosphorylation, enhanced expression of the inhibitor of apoptosis proteins (XIAP and Livin) and suppression of the proapoptotic markers (caspase 9, caspase 3 and PARP). CONCLUSIONS: This is the first report to demonstrate fascin involvement in breast cancer chemotherapeutic resistance, supporting the development of fascin-targeting drugs for better treatment of chemoresistance breast cancer.
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spelling pubmed-42000932014-10-21 Fascin is involved in the chemotherapeutic resistance of breast cancer cells predominantly via the PI3K/Akt pathway Ghebeh, H Al-Khaldi, S Olabi, S Al-Dhfyan, A Al-Mohanna, F Barnawi, R Tulbah, A Al-Tweigeri, T Ajarim, D Al-Alwan, M Br J Cancer Translational Therapeutics BACKGROUND: A major therapeutic challenge for breast cancer is the ability of cancer cells to evade killing of conventional chemotherapeutic agents. We have recently reported the actin-bundling protein (fascin) as a major regulator of breast cancer metastasis and survival. METHODS: Survival of breast cancer patients that received chemotherapy and xenograft tumour model was used to assess the effect of chemotherapy on fascin-positive and -negative breast cancer cells. Molecular and cellular assays were used to gain in-depth understanding of the relationship between fascin and chemoresistance. RESULTS: We showed a significant correlation between fascin expression and shorter survival in breast cancer patients who received chemotherapy. In xenograft experiments, fascin-positive cancer cells displayed significantly more resistance to chemotherapy-mediated apoptotic cell death than fascin-negative counterparts. This increased chemoresistance was at least partially mediated through PI3K/Akt signalling, and was paralleled by increased FAK phosphorylation, enhanced expression of the inhibitor of apoptosis proteins (XIAP and Livin) and suppression of the proapoptotic markers (caspase 9, caspase 3 and PARP). CONCLUSIONS: This is the first report to demonstrate fascin involvement in breast cancer chemotherapeutic resistance, supporting the development of fascin-targeting drugs for better treatment of chemoresistance breast cancer. Nature Publishing Group 2014-10-14 2014-08-12 /pmc/articles/PMC4200093/ /pubmed/25117814 http://dx.doi.org/10.1038/bjc.2014.453 Text en Copyright © 2014 Cancer Research UK http://creativecommons.org/licenses/by-nc-sa/3.0/ This work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
spellingShingle Translational Therapeutics
Ghebeh, H
Al-Khaldi, S
Olabi, S
Al-Dhfyan, A
Al-Mohanna, F
Barnawi, R
Tulbah, A
Al-Tweigeri, T
Ajarim, D
Al-Alwan, M
Fascin is involved in the chemotherapeutic resistance of breast cancer cells predominantly via the PI3K/Akt pathway
title Fascin is involved in the chemotherapeutic resistance of breast cancer cells predominantly via the PI3K/Akt pathway
title_full Fascin is involved in the chemotherapeutic resistance of breast cancer cells predominantly via the PI3K/Akt pathway
title_fullStr Fascin is involved in the chemotherapeutic resistance of breast cancer cells predominantly via the PI3K/Akt pathway
title_full_unstemmed Fascin is involved in the chemotherapeutic resistance of breast cancer cells predominantly via the PI3K/Akt pathway
title_short Fascin is involved in the chemotherapeutic resistance of breast cancer cells predominantly via the PI3K/Akt pathway
title_sort fascin is involved in the chemotherapeutic resistance of breast cancer cells predominantly via the pi3k/akt pathway
topic Translational Therapeutics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200093/
https://www.ncbi.nlm.nih.gov/pubmed/25117814
http://dx.doi.org/10.1038/bjc.2014.453
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