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CXCR4 activation maintains a stem cell population in tamoxifen-resistant breast cancer cells through AhR signalling

BACKGROUND: Tamoxifen is commonly used for breast cancer therapy. However, tamoxifen resistance is an important clinical problem. Continuous treatment with conventional therapy may contribute to cancer progression in recurring cancers through the accumulation of drug-resistant cancer progenitors. ME...

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Autores principales: Dubrovska, A, Hartung, A, Bouchez, L C, Walker, J R, Reddy, V A, Cho, C Y, Schultz, P G
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3389396/
https://www.ncbi.nlm.nih.gov/pubmed/22644306
http://dx.doi.org/10.1038/bjc.2012.105
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author Dubrovska, A
Hartung, A
Bouchez, L C
Walker, J R
Reddy, V A
Cho, C Y
Schultz, P G
author_facet Dubrovska, A
Hartung, A
Bouchez, L C
Walker, J R
Reddy, V A
Cho, C Y
Schultz, P G
author_sort Dubrovska, A
collection PubMed
description BACKGROUND: Tamoxifen is commonly used for breast cancer therapy. However, tamoxifen resistance is an important clinical problem. Continuous treatment with conventional therapy may contribute to cancer progression in recurring cancers through the accumulation of drug-resistant cancer progenitors. METHODS: To investigate signalling mechanisms important for the maintenance and viability of drug-resistant cancer progenitors, we used microarray analysis, PCR array for genes involved in cancer drug resistance and metabolism, flow cytometry, soft agar colony formation assay, in vivo tumourigenicity assay and immunohistochemical analysis using tamoxifen-sensitive and tamoxifen-resistant breast cancer MCF7 cells. RESULTS: Downregulation of CXCR4 signalling by small molecule antagonist AMD3100 specifically inhibits growth of progenitor cell population in MCF7(TAM-R) cells both in vitro and in vivo. Microarray analysis revealed aryl hydrocarbon receptor (AhR) signalling as one of the top networks that is differentially regulated in MCF7(TAM-R) and MCF7 xenograft tumours treated with AMD3100. Further, small molecule antagonists of AhR signalling specifically inhibit the progenitor population in MCF7(TAM-R) cells and growth of MCF7(TAM-R) xenografts in vivo. CONCLUSION: The chemokine receptor CXCR4 maintains a cancer progenitor population in tamoxifen-resistant MCF7 cells through AhR signalling and could be a putative target for the treatment of tamoxifen-resistant breast cancers.
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spelling pubmed-33893962013-06-26 CXCR4 activation maintains a stem cell population in tamoxifen-resistant breast cancer cells through AhR signalling Dubrovska, A Hartung, A Bouchez, L C Walker, J R Reddy, V A Cho, C Y Schultz, P G Br J Cancer Translational Therapeutics BACKGROUND: Tamoxifen is commonly used for breast cancer therapy. However, tamoxifen resistance is an important clinical problem. Continuous treatment with conventional therapy may contribute to cancer progression in recurring cancers through the accumulation of drug-resistant cancer progenitors. METHODS: To investigate signalling mechanisms important for the maintenance and viability of drug-resistant cancer progenitors, we used microarray analysis, PCR array for genes involved in cancer drug resistance and metabolism, flow cytometry, soft agar colony formation assay, in vivo tumourigenicity assay and immunohistochemical analysis using tamoxifen-sensitive and tamoxifen-resistant breast cancer MCF7 cells. RESULTS: Downregulation of CXCR4 signalling by small molecule antagonist AMD3100 specifically inhibits growth of progenitor cell population in MCF7(TAM-R) cells both in vitro and in vivo. Microarray analysis revealed aryl hydrocarbon receptor (AhR) signalling as one of the top networks that is differentially regulated in MCF7(TAM-R) and MCF7 xenograft tumours treated with AMD3100. Further, small molecule antagonists of AhR signalling specifically inhibit the progenitor population in MCF7(TAM-R) cells and growth of MCF7(TAM-R) xenografts in vivo. CONCLUSION: The chemokine receptor CXCR4 maintains a cancer progenitor population in tamoxifen-resistant MCF7 cells through AhR signalling and could be a putative target for the treatment of tamoxifen-resistant breast cancers. Nature Publishing Group 2012-06-26 2012-05-29 /pmc/articles/PMC3389396/ /pubmed/22644306 http://dx.doi.org/10.1038/bjc.2012.105 Text en Copyright © 2012 Cancer Research UK https://creativecommons.org/licenses/by-nc-sa/3.0/From twelve months after its original publication, 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
Dubrovska, A
Hartung, A
Bouchez, L C
Walker, J R
Reddy, V A
Cho, C Y
Schultz, P G
CXCR4 activation maintains a stem cell population in tamoxifen-resistant breast cancer cells through AhR signalling
title CXCR4 activation maintains a stem cell population in tamoxifen-resistant breast cancer cells through AhR signalling
title_full CXCR4 activation maintains a stem cell population in tamoxifen-resistant breast cancer cells through AhR signalling
title_fullStr CXCR4 activation maintains a stem cell population in tamoxifen-resistant breast cancer cells through AhR signalling
title_full_unstemmed CXCR4 activation maintains a stem cell population in tamoxifen-resistant breast cancer cells through AhR signalling
title_short CXCR4 activation maintains a stem cell population in tamoxifen-resistant breast cancer cells through AhR signalling
title_sort cxcr4 activation maintains a stem cell population in tamoxifen-resistant breast cancer cells through ahr signalling
topic Translational Therapeutics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3389396/
https://www.ncbi.nlm.nih.gov/pubmed/22644306
http://dx.doi.org/10.1038/bjc.2012.105
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