Fractionated irradiation of MCF7 breast cancer cells rewires a gene regulatory circuit towards a treatment-resistant stemness phenotype

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Fractionated irradiation of MCF7 breast cancer cells rewires a gene regulatory circuit towards a treatment-resistant stemness phenotype. / Inalegwu, Auchi; Cuypers, Bart; Claesen, Jürgen; Janssen, Ann; Coolkens, Amelie; Baatout, Sarah; De Vos, Winnok H.; Quintens, Roel.

In: Molecular Oncology, 05.05.2022, p. 1-26.

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@article{283b722c9be0422195c58f75905d438e,
title = "Fractionated irradiation of MCF7 breast cancer cells rewires a gene regulatory circuit towards a treatment-resistant stemness phenotype",
abstract = "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 proposethat these phenotypic traits render breast cancer cells more radioresistant but may at the same time serve as potential targets for combination therapies. ",
keywords = "Breast cancer, Circular RNA, Radioresistance, Relapse-free survival, Stemness, Tamoxifen resitance",
author = "Auchi Inalegwu and Bart Cuypers and J{\"u}rgen Claesen and Ann Janssen and Amelie Coolkens and Sarah Baatout and {De Vos}, {Winnok H.} and Roel Quintens",
note = "Score=10",
year = "2022",
month = may,
day = "5",
doi = "10.1002/1878-0261.13226",
language = "English",
pages = "1--26",
journal = "Molecular Oncology",
issn = "1574-7891",
publisher = "Wiley",

}

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TY - JOUR

T1 - Fractionated irradiation of MCF7 breast cancer cells rewires a gene regulatory circuit towards a treatment-resistant stemness phenotype

AU - Inalegwu, Auchi

AU - Cuypers, Bart

AU - Claesen, Jürgen

AU - Janssen, Ann

AU - Coolkens, Amelie

AU - Baatout, Sarah

AU - De Vos, Winnok H.

AU - Quintens, Roel

N1 - Score=10

PY - 2022/5/5

Y1 - 2022/5/5

N2 - 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 proposethat these phenotypic traits render breast cancer cells more radioresistant but may at the same time serve as potential targets for combination therapies.

AB - 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 proposethat these phenotypic traits render breast cancer cells more radioresistant but may at the same time serve as potential targets for combination therapies.

KW - Breast cancer

KW - Circular RNA

KW - Radioresistance

KW - Relapse-free survival

KW - Stemness

KW - Tamoxifen resitance

UR - https://ecm.sckcen.be/OTCS/llisapi.dll?func=ll&objId=49612203&objAction=download

U2 - 10.1002/1878-0261.13226

DO - 10.1002/1878-0261.13226

M3 - Article

SP - 1

EP - 26

JO - Molecular Oncology

JF - Molecular Oncology

SN - 1574-7891

ER -

ID: 7729688