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IRAK2 Downregulation in Triple-Negative Breast Cancer Cells Decreases Cellular Growth In Vitro and Delays Tumour Progression in Murine Models

Breast cancer stem cells (BCSCs) are responsible for tumour recurrence and therapy resistance. We have established primary BCSC cultures from human tumours of triple-negative breast cancer (TNBC), a subgroup of breast cancer likely driven by BCSCs. Primary BCSCs produce xenografts that phenocopy the...

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Autores principales: Ferraro, Francesca, Steinle, Anja, Narasimhan, Harini, Bleilevens, Andreas, Stolzenberg, Paula-Marie, Braunschweig, Till, Stickeler, Elmar, Maurer, Jochen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9917074/
https://www.ncbi.nlm.nih.gov/pubmed/36768848
http://dx.doi.org/10.3390/ijms24032520
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author Ferraro, Francesca
Steinle, Anja
Narasimhan, Harini
Bleilevens, Andreas
Stolzenberg, Paula-Marie
Braunschweig, Till
Stickeler, Elmar
Maurer, Jochen
author_facet Ferraro, Francesca
Steinle, Anja
Narasimhan, Harini
Bleilevens, Andreas
Stolzenberg, Paula-Marie
Braunschweig, Till
Stickeler, Elmar
Maurer, Jochen
author_sort Ferraro, Francesca
collection PubMed
description Breast cancer stem cells (BCSCs) are responsible for tumour recurrence and therapy resistance. We have established primary BCSC cultures from human tumours of triple-negative breast cancer (TNBC), a subgroup of breast cancer likely driven by BCSCs. Primary BCSCs produce xenografts that phenocopy the tumours of origin, making them an ideal model for studying breast cancer treatment options. In the TNBC cell line MDA-MB-468, we previously screened kinases whose depletion elicited a differentiation response, among which IRAK2 was identified. Because primary BCSCs are enriched in IRAK2, we wondered whether IRAK2 downregulation might affect cellular growth. IRAK2 was downregulated in primary BCSCs and MDA-MB-468 by lentiviral delivery of shRNA, causing a decrease in cellular proliferation and sphere-forming capacity. When orthotopically transplanted into immunocompromised mice, IRAK2 knockdown cells produced smaller xenografts than control cells. At the molecular level, IRAK2 downregulation reduced NF-κB and ERK phosphorylation, IL-6 and cyclin D1 expression, ERN1 signalling and autophagy in a cell line-dependent way. Overall, IRAK2 downregulation decreased cellular aggressive growth and pathways often exploited by cancer cells to endure stress; therefore, IRAK2 may be considered an interesting target to compromise TNBC progression.
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spelling pubmed-99170742023-02-11 IRAK2 Downregulation in Triple-Negative Breast Cancer Cells Decreases Cellular Growth In Vitro and Delays Tumour Progression in Murine Models Ferraro, Francesca Steinle, Anja Narasimhan, Harini Bleilevens, Andreas Stolzenberg, Paula-Marie Braunschweig, Till Stickeler, Elmar Maurer, Jochen Int J Mol Sci Article Breast cancer stem cells (BCSCs) are responsible for tumour recurrence and therapy resistance. We have established primary BCSC cultures from human tumours of triple-negative breast cancer (TNBC), a subgroup of breast cancer likely driven by BCSCs. Primary BCSCs produce xenografts that phenocopy the tumours of origin, making them an ideal model for studying breast cancer treatment options. In the TNBC cell line MDA-MB-468, we previously screened kinases whose depletion elicited a differentiation response, among which IRAK2 was identified. Because primary BCSCs are enriched in IRAK2, we wondered whether IRAK2 downregulation might affect cellular growth. IRAK2 was downregulated in primary BCSCs and MDA-MB-468 by lentiviral delivery of shRNA, causing a decrease in cellular proliferation and sphere-forming capacity. When orthotopically transplanted into immunocompromised mice, IRAK2 knockdown cells produced smaller xenografts than control cells. At the molecular level, IRAK2 downregulation reduced NF-κB and ERK phosphorylation, IL-6 and cyclin D1 expression, ERN1 signalling and autophagy in a cell line-dependent way. Overall, IRAK2 downregulation decreased cellular aggressive growth and pathways often exploited by cancer cells to endure stress; therefore, IRAK2 may be considered an interesting target to compromise TNBC progression. MDPI 2023-01-28 /pmc/articles/PMC9917074/ /pubmed/36768848 http://dx.doi.org/10.3390/ijms24032520 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ferraro, Francesca
Steinle, Anja
Narasimhan, Harini
Bleilevens, Andreas
Stolzenberg, Paula-Marie
Braunschweig, Till
Stickeler, Elmar
Maurer, Jochen
IRAK2 Downregulation in Triple-Negative Breast Cancer Cells Decreases Cellular Growth In Vitro and Delays Tumour Progression in Murine Models
title IRAK2 Downregulation in Triple-Negative Breast Cancer Cells Decreases Cellular Growth In Vitro and Delays Tumour Progression in Murine Models
title_full IRAK2 Downregulation in Triple-Negative Breast Cancer Cells Decreases Cellular Growth In Vitro and Delays Tumour Progression in Murine Models
title_fullStr IRAK2 Downregulation in Triple-Negative Breast Cancer Cells Decreases Cellular Growth In Vitro and Delays Tumour Progression in Murine Models
title_full_unstemmed IRAK2 Downregulation in Triple-Negative Breast Cancer Cells Decreases Cellular Growth In Vitro and Delays Tumour Progression in Murine Models
title_short IRAK2 Downregulation in Triple-Negative Breast Cancer Cells Decreases Cellular Growth In Vitro and Delays Tumour Progression in Murine Models
title_sort irak2 downregulation in triple-negative breast cancer cells decreases cellular growth in vitro and delays tumour progression in murine models
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9917074/
https://www.ncbi.nlm.nih.gov/pubmed/36768848
http://dx.doi.org/10.3390/ijms24032520
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