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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| Format: | Article |
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MDPI AG
2023-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/3/2520 |
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| author | Francesca Ferraro Anja Steinle Harini Narasimhan Andreas Bleilevens Paula-Marie Stolzenberg Till Braunschweig Elmar Stickeler Jochen Maurer |
| author_facet | Francesca Ferraro Anja Steinle Harini Narasimhan Andreas Bleilevens Paula-Marie Stolzenberg Till Braunschweig Elmar Stickeler Jochen Maurer |
| author_sort | Francesca Ferraro |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-11T09:40:53Z |
| format | Article |
| id | doaj.art-6ee349a5a80f48f1a2303f14a53be898 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T09:40:53Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-6ee349a5a80f48f1a2303f14a53be8982023-11-16T16:58:32ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-01-01243252010.3390/ijms24032520IRAK2 Downregulation in Triple-Negative Breast Cancer Cells Decreases Cellular Growth In Vitro and Delays Tumour Progression in Murine ModelsFrancesca Ferraro0Anja Steinle1Harini Narasimhan2Andreas Bleilevens3Paula-Marie Stolzenberg4Till Braunschweig5Elmar Stickeler6Jochen Maurer7Department of Obstetrics and Gynecology, University Hospital Aachen (UKA), D-52074 Aachen, GermanyDepartment of Obstetrics and Gynecology, University Hospital Aachen (UKA), D-52074 Aachen, GermanyDepartment of Obstetrics and Gynecology, University Hospital Aachen (UKA), D-52074 Aachen, GermanyDepartment of Obstetrics and Gynecology, University Hospital Aachen (UKA), D-52074 Aachen, GermanyDepartment of Obstetrics and Gynecology, University Hospital Aachen (UKA), D-52074 Aachen, GermanyPathology Institute, University Hospital Aachen (UKA), D-52074 Aachen, GermanyDepartment of Obstetrics and Gynecology, University Hospital Aachen (UKA), D-52074 Aachen, GermanyDepartment of Obstetrics and Gynecology, University Hospital Aachen (UKA), D-52074 Aachen, GermanyBreast 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.https://www.mdpi.com/1422-0067/24/3/2520IRAK2NF-κBERKtriple-negative breast cancerbreast cancer stem cellsendoplasmic reticulum stress |
| spellingShingle | Francesca Ferraro Anja Steinle Harini Narasimhan Andreas Bleilevens Paula-Marie Stolzenberg Till Braunschweig Elmar Stickeler Jochen Maurer IRAK2 Downregulation in Triple-Negative Breast Cancer Cells Decreases Cellular Growth In Vitro and Delays Tumour Progression in Murine Models International Journal of Molecular Sciences IRAK2 NF-κB ERK triple-negative breast cancer breast cancer stem cells endoplasmic reticulum stress |
| 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 | IRAK2 NF-κB ERK triple-negative breast cancer breast cancer stem cells endoplasmic reticulum stress |
| url | https://www.mdpi.com/1422-0067/24/3/2520 |
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