Fractionated irradiation of MCF7 breast cancer cells rewires a gene regulatory circuit towards a treatment‐resistant stemness phenotype. Issue 19 (15th June 2022)

• Record Type: Journal Article
• Authors: Inalegwu, Auchi; Cuypers, Bart; Claesen, Jürgen; Janssen, Ann; Coolkens, Amelie; Baatout, Sarah; Laukens, Kris; De Vos, Winnok H.; Quintens, Roel
• Is Part Of: Molecular oncology. Volume 16:Issue 19(2022)
• Page Start: 3410
• Page End: 3435
• Publication Date: 2022-06-15
• Subjects: breast cancer -- circular RNA -- radioresistance -- relapse‐free survival -- stemness -- tamoxifen resistance; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.13226
• Languages: English
• ISSNs: 1574-7891

Abstract

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 propose that these phenotypic traits render breast cancer cells more radioresistant but may at the same time serve as potential targets for combination therapies. Abstract : Fractionated irradiation induces a treatment‐resistant stemness phenotype underpinned by interaction between competing endogenous RNAs with both tumor‐promoting and tumor‐suppressing function. Results support cross‐resistance of radioresistant MCF7 breast cancer cells to tamoxifen and presents a gene regulatory circuit associated with treatment resistance and survival in breast cancer patients, that could be evaluated for the discovery of novel targeted therapeutic strategies.