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Open AccessArticle

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

1
Drug Delivery and Targeting Group, Molecular Biology and Biochemistry Research Centre for Nanomedicine (CIBBIM-Nanomedicine), Vall d’Hebron Institut de Recerca, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
2
Networking Research Centre for Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, 28029 Madrid, Spain
3
Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, Vall d’Hebron Institut de Recerca, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
4
Functional Validation & Preclinical Research (FVPR), CIBBIM-Nanomedicine, Vall d’Hebron Institut de Recerca, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2019, 11(8), 1058; https://doi.org/10.3390/cancers11081058
Received: 15 June 2019 / Revised: 10 July 2019 / Accepted: 22 July 2019 / Published: 26 July 2019
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. View Full-Text
Keywords: cancer stem cells (CSC); dynamic phenotype; epithelial-to-mesenchymal transition (EMT); AKT2 targeting cancer stem cells (CSC); dynamic phenotype; epithelial-to-mesenchymal transition (EMT); AKT2 targeting
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Gener, P.; Rafael, D.; Seras-Franzoso, J.; Perez, A.; Alamo Pindado, L.; Casas, G.; Arango, D.; Fernández, Y.; Díaz-Riascos, Z.V.; Abasolo, I.; Schwartz, S., Jr. Pivotal Role of AKT2 during Dynamic Phenotypic Change of Breast Cancer Stem Cells. Cancers 2019, 11, 1058.

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