Fractionated irradiation of MCF7 breast cancer cells rewires a gene regulatory circuit towards a treatment‐resistant stemness phenotype
Radiotherapy is the standard of care for breast cancer. However, surviving radioresistant cells can repopulate following treatment and provoke relapse. Better understanding of the molecular mechanisms of radiation resistance may help to improve treatment of radioresistant tumours. To emulate radiati...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-10-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.13226 |
| _version_ | 1817982657059880960 |
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| author | Auchi Inalegwu Bart Cuypers Jürgen Claesen Ann Janssen Amelie Coolkens Sarah Baatout Kris Laukens Winnok H. De Vos Roel Quintens |
| author_facet | Auchi Inalegwu Bart Cuypers Jürgen Claesen Ann Janssen Amelie Coolkens Sarah Baatout Kris Laukens Winnok H. De Vos Roel Quintens |
| author_sort | Auchi Inalegwu |
| collection | DOAJ |
| description | Radiotherapy is the standard of care for breast cancer. However, surviving radioresistant cells can repopulate following treatment and provoke relapse. Better understanding of the molecular mechanisms of radiation resistance may help to improve treatment of radioresistant tumours. To emulate radiation therapy at the cellular level, we exposed MCF7 breast cancer cells to daily radiation doses of 2 Gy up to an accumulated dose of 20 Gy. Fractionally irradiated cells (FIR20) displayed increased clonogenic survival and population doubling time as compared with age‐matched sham‐irradiated cells and untreated parental MCF7 cells. RNA‐sequencing revealed a core signature of 229 mRNAs and 7 circular RNAs of which the expression was significantly altered in FIR20 cells. Dysregulation of several top genes was mirrored at the protein level. The FIR20 cell transcriptome overlapped significantly with canonical radiation response signatures and demonstrated a remarkable commonality with radiation and endocrine therapy resistance expression profiles, suggesting crosstalk between both acquired resistance pathways, as indicated by reduced sensitivity to tamoxifen cytotoxicity of FIR20 cells. Using predictive analyses and functional enrichment, we identified a gene‐regulatory network that promotes stemness and inflammatory signalling in FIR20 cells. We propose that these phenotypic traits render breast cancer cells more radioresistant but may at the same time serve as potential targets for combination therapies. |
| first_indexed | 2024-04-13T23:24:22Z |
| format | Article |
| id | doaj.art-65577c9f7e304b9b8713ac0344f9c9d7 |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-04-13T23:24:22Z |
| publishDate | 2022-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-65577c9f7e304b9b8713ac0344f9c9d72022-12-22T02:25:08ZengWileyMolecular Oncology1574-78911878-02612022-10-0116193410343510.1002/1878-0261.13226Fractionated irradiation of MCF7 breast cancer cells rewires a gene regulatory circuit towards a treatment‐resistant stemness phenotypeAuchi Inalegwu0Bart Cuypers1Jürgen Claesen2Ann Janssen3Amelie Coolkens4Sarah Baatout5Kris Laukens6Winnok H. De Vos7Roel Quintens8Radiobiology Unit, SCK CEN Belgian Nuclear Research Centre Mol BelgiumAdrem Data Lab, Department of Computer Science University of Antwerp BelgiumDepartment of Epidemiology and Data Science, Amsterdam UMC VU Amsterdam The NetherlandsRadiobiology Unit, SCK CEN Belgian Nuclear Research Centre Mol BelgiumRadiobiology Unit, SCK CEN Belgian Nuclear Research Centre Mol BelgiumRadiobiology Unit, SCK CEN Belgian Nuclear Research Centre Mol BelgiumAdrem Data Lab, Department of Computer Science University of Antwerp BelgiumDepartment of Veterinary Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences University of Antwerp BelgiumRadiobiology Unit, SCK CEN Belgian Nuclear Research Centre Mol BelgiumRadiotherapy is the standard of care for breast cancer. However, surviving radioresistant cells can repopulate following treatment and provoke relapse. Better understanding of the molecular mechanisms of radiation resistance may help to improve treatment of radioresistant tumours. To emulate radiation therapy at the cellular level, we exposed MCF7 breast cancer cells to daily radiation doses of 2 Gy up to an accumulated dose of 20 Gy. Fractionally irradiated cells (FIR20) displayed increased clonogenic survival and population doubling time as compared with age‐matched sham‐irradiated cells and untreated parental MCF7 cells. RNA‐sequencing revealed a core signature of 229 mRNAs and 7 circular RNAs of which the expression was significantly altered in FIR20 cells. Dysregulation of several top genes was mirrored at the protein level. The FIR20 cell transcriptome overlapped significantly with canonical radiation response signatures and demonstrated a remarkable commonality with radiation and endocrine therapy resistance expression profiles, suggesting crosstalk between both acquired resistance pathways, as indicated by reduced sensitivity to tamoxifen cytotoxicity of FIR20 cells. Using predictive analyses and functional enrichment, we identified a gene‐regulatory network that promotes stemness and inflammatory signalling in FIR20 cells. We propose that these phenotypic traits render breast cancer cells more radioresistant but may at the same time serve as potential targets for combination therapies.https://doi.org/10.1002/1878-0261.13226breast cancercircular RNAradioresistancerelapse‐free survivalstemnesstamoxifen resistance |
| spellingShingle | Auchi Inalegwu Bart Cuypers Jürgen Claesen Ann Janssen Amelie Coolkens Sarah Baatout Kris Laukens Winnok H. De Vos Roel Quintens Fractionated irradiation of MCF7 breast cancer cells rewires a gene regulatory circuit towards a treatment‐resistant stemness phenotype Molecular Oncology breast cancer circular RNA radioresistance relapse‐free survival stemness tamoxifen resistance |
| title | Fractionated irradiation of MCF7 breast cancer cells rewires a gene regulatory circuit towards a treatment‐resistant stemness phenotype |
| title_full | Fractionated irradiation of MCF7 breast cancer cells rewires a gene regulatory circuit towards a treatment‐resistant stemness phenotype |
| title_fullStr | Fractionated irradiation of MCF7 breast cancer cells rewires a gene regulatory circuit towards a treatment‐resistant stemness phenotype |
| title_full_unstemmed | Fractionated irradiation of MCF7 breast cancer cells rewires a gene regulatory circuit towards a treatment‐resistant stemness phenotype |
| title_short | Fractionated irradiation of MCF7 breast cancer cells rewires a gene regulatory circuit towards a treatment‐resistant stemness phenotype |
| title_sort | fractionated irradiation of mcf7 breast cancer cells rewires a gene regulatory circuit towards a treatment resistant stemness phenotype |
| topic | breast cancer circular RNA radioresistance relapse‐free survival stemness tamoxifen resistance |
| url | https://doi.org/10.1002/1878-0261.13226 |
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