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AXL induces epithelial to mesenchymal transition and regulates the function of breast cancer stem cells

Despite significant progress in the treatment of breast cancer particularly through the use of targeted therapy, relapse and chemo-resistance remain a major hindrance to the fight to minimize the burden of the disease. It is becoming increasingly clear that a rare subpopulation of cells known as can...

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Autores principales: Asiedu, Michael K., Beauchamp-Perez, Francis D., Ingle, James N., Behrens, Marshall D., Radisky, Derek C., Knutson, Keith L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994701/
https://www.ncbi.nlm.nih.gov/pubmed/23474758
http://dx.doi.org/10.1038/onc.2013.57
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author Asiedu, Michael K.
Beauchamp-Perez, Francis D.
Ingle, James N.
Behrens, Marshall D.
Radisky, Derek C.
Knutson, Keith L.
author_facet Asiedu, Michael K.
Beauchamp-Perez, Francis D.
Ingle, James N.
Behrens, Marshall D.
Radisky, Derek C.
Knutson, Keith L.
author_sort Asiedu, Michael K.
collection PubMed
description Despite significant progress in the treatment of breast cancer particularly through the use of targeted therapy, relapse and chemo-resistance remain a major hindrance to the fight to minimize the burden of the disease. It is becoming increasingly clear that a rare subpopulation of cells known as cancer stem cells (CSC), able to be generated through epithelial to mesenchymal transition (EMT) and capable of tumor initiation and self-renewal, contributes to treatment resistance and metastases. This means that a more effective therapy should target both the chemoresistant CSCs and the proliferating epithelial cells that give rise to them in order to reverse EMT and attenuate their conversion to CSCs. Here, we demonstrate a novel function of AXL in acting upstream to induce EMT in normal and immortalized human mammary epithelial cells in an apparent positive feedback loop mechanism and regulate breast CSC (BCSC) self-renewal and chemoresistance. Downregulation of AXL using MP470 (amuvatinib) reversed EMT in mesenchymal normal human mammary epithelial cells and murine BCSCs attenuating self-renewal and restored chemosensitivity of the BCSCs. AXL expression was also found to be associated with expression of stem cell genes, regulation of metastases genes, increased tumorigenicity, and was important for BCSC invasion and migration. Inactivation of AXL also led to downregulation of NFκB pathway and reduced tumor formation in vivo. Together, our data suggest that targeted therapy against AXL, in combination with systemic therapies, has the potential to improve response to anti-cancer therapies and to reduce breast cancer recurrence and metastases.
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spelling pubmed-39947012014-09-06 AXL induces epithelial to mesenchymal transition and regulates the function of breast cancer stem cells Asiedu, Michael K. Beauchamp-Perez, Francis D. Ingle, James N. Behrens, Marshall D. Radisky, Derek C. Knutson, Keith L. Oncogene Article Despite significant progress in the treatment of breast cancer particularly through the use of targeted therapy, relapse and chemo-resistance remain a major hindrance to the fight to minimize the burden of the disease. It is becoming increasingly clear that a rare subpopulation of cells known as cancer stem cells (CSC), able to be generated through epithelial to mesenchymal transition (EMT) and capable of tumor initiation and self-renewal, contributes to treatment resistance and metastases. This means that a more effective therapy should target both the chemoresistant CSCs and the proliferating epithelial cells that give rise to them in order to reverse EMT and attenuate their conversion to CSCs. Here, we demonstrate a novel function of AXL in acting upstream to induce EMT in normal and immortalized human mammary epithelial cells in an apparent positive feedback loop mechanism and regulate breast CSC (BCSC) self-renewal and chemoresistance. Downregulation of AXL using MP470 (amuvatinib) reversed EMT in mesenchymal normal human mammary epithelial cells and murine BCSCs attenuating self-renewal and restored chemosensitivity of the BCSCs. AXL expression was also found to be associated with expression of stem cell genes, regulation of metastases genes, increased tumorigenicity, and was important for BCSC invasion and migration. Inactivation of AXL also led to downregulation of NFκB pathway and reduced tumor formation in vivo. Together, our data suggest that targeted therapy against AXL, in combination with systemic therapies, has the potential to improve response to anti-cancer therapies and to reduce breast cancer recurrence and metastases. 2013-03-11 2014-03-06 /pmc/articles/PMC3994701/ /pubmed/23474758 http://dx.doi.org/10.1038/onc.2013.57 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Asiedu, Michael K.
Beauchamp-Perez, Francis D.
Ingle, James N.
Behrens, Marshall D.
Radisky, Derek C.
Knutson, Keith L.
AXL induces epithelial to mesenchymal transition and regulates the function of breast cancer stem cells
title AXL induces epithelial to mesenchymal transition and regulates the function of breast cancer stem cells
title_full AXL induces epithelial to mesenchymal transition and regulates the function of breast cancer stem cells
title_fullStr AXL induces epithelial to mesenchymal transition and regulates the function of breast cancer stem cells
title_full_unstemmed AXL induces epithelial to mesenchymal transition and regulates the function of breast cancer stem cells
title_short AXL induces epithelial to mesenchymal transition and regulates the function of breast cancer stem cells
title_sort axl induces epithelial to mesenchymal transition and regulates the function of breast cancer stem cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994701/
https://www.ncbi.nlm.nih.gov/pubmed/23474758
http://dx.doi.org/10.1038/onc.2013.57
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