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Pivotal Role of AKT2 during Dynamic Phenotypic Change of Breast Cancer Stem Cells

Therapeutic resistance seen in aggressive forms of breast cancer remains challenging for current treatments. More than half of the patients suffer from a disease relapse, most of them with distant metastases. Cancer maintenance, resistance to therapy, and metastatic disease seem to be sustained by t...

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Autores principales: Gener, Petra, Rafael, Diana, Seras-Franzoso, Joaquin, Perez, Anna, Alamo Pindado, Luis, Casas, Glòria, Arango, Diego, Fernández, Yolanda, Díaz-Riascos, Zamira V., Abasolo, Ibane, Schwartz, Simó
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721305/
https://www.ncbi.nlm.nih.gov/pubmed/31357505
http://dx.doi.org/10.3390/cancers11081058
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author Gener, Petra
Rafael, Diana
Seras-Franzoso, Joaquin
Perez, Anna
Alamo Pindado, Luis
Casas, Glòria
Arango, Diego
Fernández, Yolanda
Díaz-Riascos, Zamira V.
Abasolo, Ibane
Schwartz, Simó
author_facet Gener, Petra
Rafael, Diana
Seras-Franzoso, Joaquin
Perez, Anna
Alamo Pindado, Luis
Casas, Glòria
Arango, Diego
Fernández, Yolanda
Díaz-Riascos, Zamira V.
Abasolo, Ibane
Schwartz, Simó
author_sort Gener, Petra
collection PubMed
description Therapeutic resistance seen in aggressive forms of breast cancer remains challenging for current treatments. More than half of the patients suffer from a disease relapse, most of them with distant metastases. Cancer maintenance, resistance to therapy, and metastatic disease seem to be sustained by the presence of cancer stem cells (CSC) within a tumor. The difficulty in targeting this subpopulation derives from their dynamic interconversion process, where CSC can differentiate to non-CSC, which in turn de-differentiate into cells with CSC properties. Using fluorescent CSC models driven by the expression of ALDH1A 1(aldehyde dehydrogenase 1A1), we confirmed this dynamic phenotypic change in MDA-MB-231 breast cancer cells and to identify Serine/Threonine Kinase 2 (AKT2) as an important player in the process. To confirm the central role of AKT2, we silenced AKT2 expression via small interfering RNA and using a chemical inhibitor (CCT128930), in both CSC and non-CSC from different cancer cell lines. Our results revealed that AKT2 inhibition effectively prevents non-CSC reversion through mesenchymal to epithelial transition, reducing invasion and colony formation ability of both, non-CSC and CSC. Further, AKT2 inhibition reduced CSC survival in low attachment conditions. Interestingly, in orthotopic tumor mouse models, high expression levels of AKT2 were detected in circulating tumor cells (CTC). These findings suggest AKT2 as a promising target for future anti-cancer therapies at three important levels: (i) Epithelial-to-mesenchymal transition (EMT) reversion and maintenance of CSC subpopulation in primary tumors, (ii) reduction of CTC and the likelihood of metastatic spread, and (iii) prevention of tumor recurrence through inhibition of CSC tumorigenic and metastatic potential.
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spelling pubmed-67213052019-09-10 Pivotal Role of AKT2 during Dynamic Phenotypic Change of Breast Cancer Stem Cells Gener, Petra Rafael, Diana Seras-Franzoso, Joaquin Perez, Anna Alamo Pindado, Luis Casas, Glòria Arango, Diego Fernández, Yolanda Díaz-Riascos, Zamira V. Abasolo, Ibane Schwartz, Simó Cancers (Basel) Article Therapeutic resistance seen in aggressive forms of breast cancer remains challenging for current treatments. More than half of the patients suffer from a disease relapse, most of them with distant metastases. Cancer maintenance, resistance to therapy, and metastatic disease seem to be sustained by the presence of cancer stem cells (CSC) within a tumor. The difficulty in targeting this subpopulation derives from their dynamic interconversion process, where CSC can differentiate to non-CSC, which in turn de-differentiate into cells with CSC properties. Using fluorescent CSC models driven by the expression of ALDH1A 1(aldehyde dehydrogenase 1A1), we confirmed this dynamic phenotypic change in MDA-MB-231 breast cancer cells and to identify Serine/Threonine Kinase 2 (AKT2) as an important player in the process. To confirm the central role of AKT2, we silenced AKT2 expression via small interfering RNA and using a chemical inhibitor (CCT128930), in both CSC and non-CSC from different cancer cell lines. Our results revealed that AKT2 inhibition effectively prevents non-CSC reversion through mesenchymal to epithelial transition, reducing invasion and colony formation ability of both, non-CSC and CSC. Further, AKT2 inhibition reduced CSC survival in low attachment conditions. Interestingly, in orthotopic tumor mouse models, high expression levels of AKT2 were detected in circulating tumor cells (CTC). These findings suggest AKT2 as a promising target for future anti-cancer therapies at three important levels: (i) Epithelial-to-mesenchymal transition (EMT) reversion and maintenance of CSC subpopulation in primary tumors, (ii) reduction of CTC and the likelihood of metastatic spread, and (iii) prevention of tumor recurrence through inhibition of CSC tumorigenic and metastatic potential. MDPI 2019-07-26 /pmc/articles/PMC6721305/ /pubmed/31357505 http://dx.doi.org/10.3390/cancers11081058 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Gener, Petra
Rafael, Diana
Seras-Franzoso, Joaquin
Perez, Anna
Alamo Pindado, Luis
Casas, Glòria
Arango, Diego
Fernández, Yolanda
Díaz-Riascos, Zamira V.
Abasolo, Ibane
Schwartz, Simó
Pivotal Role of AKT2 during Dynamic Phenotypic Change of Breast Cancer Stem Cells
title Pivotal Role of AKT2 during Dynamic Phenotypic Change of Breast Cancer Stem Cells
title_full Pivotal Role of AKT2 during Dynamic Phenotypic Change of Breast Cancer Stem Cells
title_fullStr Pivotal Role of AKT2 during Dynamic Phenotypic Change of Breast Cancer Stem Cells
title_full_unstemmed Pivotal Role of AKT2 during Dynamic Phenotypic Change of Breast Cancer Stem Cells
title_short Pivotal Role of AKT2 during Dynamic Phenotypic Change of Breast Cancer Stem Cells
title_sort pivotal role of akt2 during dynamic phenotypic change of breast cancer stem cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721305/
https://www.ncbi.nlm.nih.gov/pubmed/31357505
http://dx.doi.org/10.3390/cancers11081058
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