Polyoxometalate inhibition of SOX2-mediated tamoxifen resistance in breast cancer
Background Increased cancer stem cell (CSC) content and SOX2 overexpression are common features in the development of resistance to therapy in hormone-dependent breast cancer, which remains an important clinical challenge. SOX2 has potential as biomarker of resistance to treatment and as therapeutic...
| Autores: | , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Universidad del País Vasco |
| Repositorio: | Addi. Archivo Digital para la Docencia y la Investigación |
| OAI Identifier: | oai:addi.ehu.eus:10810/69470 |
| Acceso en línea: | http://hdl.handle.net/10810/69470 |
| Access Level: | acceso abierto |
| Palabra clave: | breast cancer cancer stem cells resistance hormone therapy SOX2 inhibition polyoxometalate |
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Polyoxometalate inhibition of SOX2-mediated tamoxifen resistance in breast cancer |
| title |
Polyoxometalate inhibition of SOX2-mediated tamoxifen resistance in breast cancer |
| spellingShingle |
Polyoxometalate inhibition of SOX2-mediated tamoxifen resistance in breast cancer Aurrekoetxea Rodríguez, Iskander breast cancer cancer stem cells resistance hormone therapy SOX2 inhibition polyoxometalate |
| title_short |
Polyoxometalate inhibition of SOX2-mediated tamoxifen resistance in breast cancer |
| title_full |
Polyoxometalate inhibition of SOX2-mediated tamoxifen resistance in breast cancer |
| title_fullStr |
Polyoxometalate inhibition of SOX2-mediated tamoxifen resistance in breast cancer |
| title_full_unstemmed |
Polyoxometalate inhibition of SOX2-mediated tamoxifen resistance in breast cancer |
| title_sort |
Polyoxometalate inhibition of SOX2-mediated tamoxifen resistance in breast cancer |
| dc.creator.none.fl_str_mv |
Aurrekoetxea Rodríguez, Iskander Lee, So Young Rabano, Miriam Gris Cárdenas, Isabel Gamboa Aldecoa, Virginia Gorroño, Irantzu Ramella Gal, Isabella Parry, Connor Kypta, Robert M. Artetxe Arretxe, Beñat Gutiérrez Zorrilla López, Juan Manuel Vivanco Ruiz, María del Mar |
| author |
Aurrekoetxea Rodríguez, Iskander |
| author_facet |
Aurrekoetxea Rodríguez, Iskander Lee, So Young Rabano, Miriam Gris Cárdenas, Isabel Gamboa Aldecoa, Virginia Gorroño, Irantzu Ramella Gal, Isabella Parry, Connor Kypta, Robert M. Artetxe Arretxe, Beñat Gutiérrez Zorrilla López, Juan Manuel Vivanco Ruiz, María del Mar |
| author_role |
author |
| author2 |
Lee, So Young Rabano, Miriam Gris Cárdenas, Isabel Gamboa Aldecoa, Virginia Gorroño, Irantzu Ramella Gal, Isabella Parry, Connor Kypta, Robert M. Artetxe Arretxe, Beñat Gutiérrez Zorrilla López, Juan Manuel Vivanco Ruiz, María del Mar |
| author2_role |
author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
breast cancer cancer stem cells resistance hormone therapy SOX2 inhibition polyoxometalate |
| topic |
breast cancer cancer stem cells resistance hormone therapy SOX2 inhibition polyoxometalate |
| description |
Background Increased cancer stem cell (CSC) content and SOX2 overexpression are common features in the development of resistance to therapy in hormone-dependent breast cancer, which remains an important clinical challenge. SOX2 has potential as biomarker of resistance to treatment and as therapeutic target, but targeting transcription factors is also challenging. Here, we examine the potential inhibitory effect of different polyoxometalate (POM) derivatives on SOX2 transcription factor in tamoxifen-resistant breast cancer cells. Methods Various POM derivatives were synthesised and characterised by infrared spectra, powder X-ray diffraction pattern and nuclear magnetic resonance spectroscopy. Estrogen receptor (ER) positive breast cancer cells, and their counterparts, which have developed resistance to the hormone therapy tamoxifen, were treated with POMs and their consequences assessed by gel retardation and chromatin immunoprecipitation to determine SOX2 binding to DNA. Effects on proliferation, migration, invasion and tumorigenicity were monitored and quantified using microscopy, clone formation, transwell, wound healing assays, flow cytometry and in vivo chick chorioallantoic membrane (CAM) models. Generation of lentiviral stable gene silencing and gene knock-out using CRISPR-Cas9 genome editing were applied to validate the inhibitory effects of the selected POM. Cancer stem cell subpopulations were quantified by mammosphere formation assays, ALDEFLUOR activity and CD44/CD24 stainings. Flow cytometry and western blotting were used to measure reactive oxygen species (ROS) and apoptosis. Results POMs blocked in vitro binding activity of endogenous SOX2. [P2W18O62]6− (PW) Wells-Dawson-type anion was the most effective at inhibiting proliferation in various cell line models of tamoxifen resistance. 10 µM PW also reduced cancer cell migration and invasion, as well as SNAI2 expression levels. Treatment of tamoxifen-resistant cells with PW impaired tumour formation by reducing CSC content, in a SOX2-dependent manner, which led to stem cell depletion in vivo. Mechanistically, PW induced formation of reactive oxygen species (ROS) and inhibited Bcl-2, leading to the death of tamoxifen-resistant cells. PW-treated tamoxifen-resistant cells showed restored sensitivity to tamoxifen. Conclusions Together, these observations highlight the potential use of PW as a SOX2 inhibitor and the therapeutic relevance of targeting SOX2 to treat tamoxifen-resistant breast cancer. |
| publishDate |
2024 |
| dc.date.none.fl_str_mv |
2024 2024 2024 |
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info:eu-repo/semantics/article |
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article |
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http://hdl.handle.net/10810/69470 |
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http://hdl.handle.net/10810/69470 |
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Inglés |
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Inglés |
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info:eu-repo/grantAgreement/MICINN/PID2022-139530NB-I00/ info:eu-repo/grantAgreement/MICINN/CEX2021-001136-S/ info:eu-repo/grantAgreement/MICINN/PID2020-118464RB-I00/ info:eu-repo/grantAgreement/MICINN/PID2020-117649RB-100/ https://biosignaling.biomedcentral.com/articles/10.1186/s12964-024-01800-w |
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info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by-nc-nd/3.0/es/ Atribución-NoComercial-SinDerivadas 3.0 España |
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openAccess |
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http://creativecommons.org/licenses/by-nc-nd/3.0/es/ Atribución-NoComercial-SinDerivadas 3.0 España |
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application/pdf |
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BMC |
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BMC |
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reponame:Addi. Archivo Digital para la Docencia y la Investigación instname:Universidad del País Vasco |
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Universidad del País Vasco |
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Addi. Archivo Digital para la Docencia y la Investigación |
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Addi. Archivo Digital para la Docencia y la Investigación |
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1869405566409900032 |
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Polyoxometalate inhibition of SOX2-mediated tamoxifen resistance in breast cancerAurrekoetxea Rodríguez, IskanderLee, So YoungRabano, MiriamGris Cárdenas, IsabelGamboa Aldecoa, VirginiaGorroño, IrantzuRamella Gal, IsabellaParry, ConnorKypta, Robert M.Artetxe Arretxe, BeñatGutiérrez Zorrilla López, Juan ManuelVivanco Ruiz, María del Marbreast cancercancer stem cellsresistancehormone therapySOX2 inhibitionpolyoxometalateBackground Increased cancer stem cell (CSC) content and SOX2 overexpression are common features in the development of resistance to therapy in hormone-dependent breast cancer, which remains an important clinical challenge. SOX2 has potential as biomarker of resistance to treatment and as therapeutic target, but targeting transcription factors is also challenging. Here, we examine the potential inhibitory effect of different polyoxometalate (POM) derivatives on SOX2 transcription factor in tamoxifen-resistant breast cancer cells. Methods Various POM derivatives were synthesised and characterised by infrared spectra, powder X-ray diffraction pattern and nuclear magnetic resonance spectroscopy. Estrogen receptor (ER) positive breast cancer cells, and their counterparts, which have developed resistance to the hormone therapy tamoxifen, were treated with POMs and their consequences assessed by gel retardation and chromatin immunoprecipitation to determine SOX2 binding to DNA. Effects on proliferation, migration, invasion and tumorigenicity were monitored and quantified using microscopy, clone formation, transwell, wound healing assays, flow cytometry and in vivo chick chorioallantoic membrane (CAM) models. Generation of lentiviral stable gene silencing and gene knock-out using CRISPR-Cas9 genome editing were applied to validate the inhibitory effects of the selected POM. Cancer stem cell subpopulations were quantified by mammosphere formation assays, ALDEFLUOR activity and CD44/CD24 stainings. Flow cytometry and western blotting were used to measure reactive oxygen species (ROS) and apoptosis. Results POMs blocked in vitro binding activity of endogenous SOX2. [P2W18O62]6− (PW) Wells-Dawson-type anion was the most effective at inhibiting proliferation in various cell line models of tamoxifen resistance. 10 µM PW also reduced cancer cell migration and invasion, as well as SNAI2 expression levels. Treatment of tamoxifen-resistant cells with PW impaired tumour formation by reducing CSC content, in a SOX2-dependent manner, which led to stem cell depletion in vivo. Mechanistically, PW induced formation of reactive oxygen species (ROS) and inhibited Bcl-2, leading to the death of tamoxifen-resistant cells. PW-treated tamoxifen-resistant cells showed restored sensitivity to tamoxifen. Conclusions Together, these observations highlight the potential use of PW as a SOX2 inhibitor and the therapeutic relevance of targeting SOX2 to treat tamoxifen-resistant breast cancer.The authors thank grant support from the Basque Government (IT1722-22 and Elkartek KK-2022/00045) and Spanish Ministry of Science, Innovation and Universities (MICINN, grant PID2022-139530NB-I00) (JMGZ). This research was also funded by Elkartek (KK-2022/00045) by the Basque Government (MdMV), and by the Spanish Ministry of Science and Innovation MCIN/AEI/https://doi.org/10.13039/501100011033 (to MdMV and RK: CEX2021-001136-S; PRE2018-087073 to IG; PID2020-118464RB-I00 to MdMV, and PID2020-117649RB-100 to RK).BMC202420242024info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10810/69470reponame:Addi. Archivo Digital para la Docencia y la Investigacióninstname:Universidad del País VascoInglésinfo:eu-repo/grantAgreement/MICINN/PID2022-139530NB-I00/info:eu-repo/grantAgreement/MICINN/CEX2021-001136-S/info:eu-repo/grantAgreement/MICINN/PID2020-118464RB-I00/info:eu-repo/grantAgreement/MICINN/PID2020-117649RB-100/https://biosignaling.biomedcentral.com/articles/10.1186/s12964-024-01800-winfo:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by-nc-nd/3.0/es/© The Author(s) 2024. This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.Atribución-NoComercial-SinDerivadas 3.0 Españaoai:addi.ehu.eus:10810/694702026-06-18T09:23:17Z |
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