Abstract
BackgroundRadiotherapy plays an important role in the multimodal treatment of breast cancer. The response of a breast tumour to radiation depends not only on its innate radiosensitivity but also on tumour repopulation by cells that have developed radioresistance. Development of effective cancer treatments will require further molecular dissection of the processes that contribute to resistance.MethodsRadioresistant cell lines were established by exposing MDA-MB-231, MCF-7 and ZR-751 parental cells to increasing weekly doses of radiation. The development of radioresistance was evaluated through proliferation and colony formation assays. Phenotypic characterisation included migration and invasion assays and immunohistochemistry. Transcriptomic data were also generated for preliminary hypothesis generation involving pathway-focused analyses.ResultsProliferation and colony formation assays confirmed radioresistance. Radioresistant cells exhibited enhanced migration and invasion, with evidence of epithelial-to-mesenchymal-transition. Significantly, acquisition of radioresistance in MCF-7 and ZR-751 cell lines resulted in a loss of expression of both ERα and PgR and an increase in EGFR expression; based on transcriptomic data they changed subtype classification from their parental luminal A to HER2-overexpressing (MCF-7 RR) and normal-like (ZR-751 RR) subtypes, indicating the extent of phenotypic changes and cellular plasticity involved in this process. Radioresistant cell lines derived from ER+ cells also showed a shift from ER to EGFR signalling pathways with increased MAPK and PI3K activity.ConclusionsThis is the first study to date that extensively describes the development and characterisation of three novel radioresistant breast cancer cell lines through both genetic and phenotypic analysis. More changes were identified between parental cells and their radioresistant derivatives in the ER+ (MCF-7 and ZR-751) compared with the ER- cell line (MDA-MB-231) model; however, multiple and likely interrelated mechanisms were identified that may contribute to the development of acquired resistance to radiotherapy.
Highlights
Radiotherapy plays an important role in the multimodal treatment of breast cancer
Development and confirmation of the acquisition of radioresistance in Oestrogen receptor (ER)+ and ER- breast cancer cell lines Radioresistant cell lines (MCF-7 RR, ZR-751 RR and MDA-MB-231 RR) were developed from their parental cell lines (MCF-7, ZR-751 and MDA-MB-231) by weekly exposure to single fractions of radiation, increasing by 0.5 Gy per week over a period of 12 weeks; cells were subsequently maintained by weekly doses of 5 Gy
Less inhibition of proliferation was seen in the RR cell lines compared to their parental cell lines when exposed to a single dose of radiation up to 10 Gy (Fig. 1b)
Summary
Radiotherapy plays an important role in the multimodal treatment of breast cancer. The response of a breast tumour to radiation depends on its innate radiosensitivity and on tumour repopulation by cells that have developed radioresistance. Despite the successful use of adjuvant RT in breast cancer, some patients will still develop loco-regional recurrences following the completion of a RT course. While tumour recurrence following RT can be due to residual disease or aggressive tumour biology, it can be due to the survival of a population of cells that either have a greater intrinsic resistance to RT (e.g. hypoxic or cancer stem cells) or develop de novo resistance. These radioresistant cells can repopulate the tumour site leading to recurrence and treatment failure
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