Radiation resistance due to high expression of miR-21 and G2/M checkpoint arrest in breast cancer cells

Radiation Oncology

Michael J Atkinson⁴  Michaela Aubele⁵  Gert Auer¹  Natalie Ludyga⁵  Herbert Braselmann²  Kristina Rappl⁵  Iria Gonzalez Vasconcellos³  Ines Höfig³  Nataša Anastasov³ 

[1] Department of Oncology and Pathology, Karolinska Institute and Hospital, Stockholm, Sweden;Research Unit of Radiation Cytogenetics, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Muenchen, Germany;Institute of Radiation Biology, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Muenchen, Germany;Radiation Biology, Institute of Radiation Oncology, Technical University Munich, Munich, Germany;Institute of Pathology, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Muenchen, Germany

关键词: G2/M checkpoint arrest;    Radiation resistance;    Breast cancer;    MiR-21;   

Others  :  1154955
DOI  :  10.1186/1748-717X-7-206

 received in 2012-06-29, accepted in 2012-11-23,  发布年份 2012

【 摘 要 】

Background

There is evidence that the extent of the G2/M arrest following irradiation is correlated with tumour cell survival and hence therapeutic success. We studied the regulation of cellular response to radiation treatment by miR-21-mediated modulation of cell cycle progression in breast cancer cells and analysed miR-21 expression in breast cancer tissue samples with long-term follow up.

Methods

The miR-21 expression levels were quantified (qRT-PCR) in a panel of 86 cases of invasive breast carcinomas in relation to metastasis free survival. The cellular radiosensitivity of human breast cancer cells after irradiation was determined comparing two cell lines (T47D and MDA-MB-361) by cell proliferation and colony forming assays. The influence of miR-21 overexpression or downregulation on cell cycle progression and G2/M checkpoint arrest after irradiation was assessed by flow cytometric analysis.

Results

The expression of miR-21 was transiently increased 8 hours after irradiation in the radioresistant T47D cells and significantly changed with lower extent in radiosensitive MDA-MB-361 cells. Anti-miR-21 treated breast cancer cells failed to exhibit the DNA damage-G2 checkpoint increase after irradiation. Apoptotic activity was significantly enhanced from 7% to 27% in T47D cells and from 18% to 30% in MDA-MB-361 cells 24 hours after 5 Gy irradiation. Additionally, we characterized expression of miR-21 in invasive breast carcinomas. In comparison to non-cancerous adjacent breast tissue, tumours samples had increased miR-21 expression that inversely correlated with the distant metastases-free survival of patients (p = 0.029).

Conclusions

Our data indicate that miR-21 expression in breast cancer cells contributes to radiation resistance by compromising cell cycle progression. These data point to the potential of combining radiotherapy with an anti-miR-21 as a potent G2/M check point inhibitor in overcoming radiation resistance of tumours.

【 授权许可】

   
2012 Anastasov et al.; licensee BioMed Central Ltd.

【 图 表 】

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