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Radiation Oncology
Published in: Radiation Oncology 1/2019

Open Access 01-12-2019 | Breast Cancer | Research

Development and characterisation of acquired radioresistant breast cancer cell lines

Authors: Mark Gray, Arran K. Turnbull, Carol Ward, James Meehan, Carlos Martínez-Pérez, Maria Bonello, Lisa Y. Pang, Simon P. Langdon, Ian H. Kunkler, Alan Murray, David Argyle

Published in: Radiation Oncology | Issue 1/2019

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Abstract

Background

Radiotherapy 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.

Methods

Radioresistant 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.

Results

Proliferation 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.

Conclusions

This 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.
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Metadata
Title
Development and characterisation of acquired radioresistant breast cancer cell lines
Authors
Mark Gray
Arran K. Turnbull
Carol Ward
James Meehan
Carlos Martínez-Pérez
Maria Bonello
Lisa Y. Pang
Simon P. Langdon
Ian H. Kunkler
Alan Murray
David Argyle
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Radiation Oncology / Issue 1/2019
Electronic ISSN: 1748-717X
DOI
https://doi.org/10.1186/s13014-019-1268-2

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