Microarray analysis of the transcriptional response to single or multiple doses of ionizing radiation in human subcutaneous fibroblasts.
OBJECTIVE
Transcriptional profiling of fibroblasts derived from breast cancer patients might improve our understanding of subcutaneous radiation-induced fibrosis. The aim of this study was to get a comprehensive overview of the changes in gene expression in subcutaneous fibroblast cell lines after various ionizing radiation (IR) schemes in order to provide information on potential targets for prevention and to suggest candidate genes for SNP association studies aimed at predicting individual risk of radiation-induced morbidity.


METHODS
Thirty different human fibroblast cell lines were included in the study, and two different radiation schemes; single dose experiments with 3.5 Gy or fractionated with 3 x 3.5 Gy. Expression analyses were performed on unexposed and exposed cells after different time points. The IR response was analyzed using the statistical method Significance Analysis of Microarrays (SAM).


RESULTS
While many of the identified genes were involved in known IR response pathways like cell cycle arrest, proliferation and detoxification, a substantial fraction of the genes were involved in processes not previously associated with IR response. Of particular interest is genes involved in ECM remodelling, Wnt signalling and IGF signalling. Many of the genes were identified after a single dose, but transcriptional changes in genes related to ROS scavenging and ECM remodelling were most profound after a fractionated scheme.


CONCLUSIONS
We have identified a number of IR response pathways in fibroblasts derived from breast cancer patients. Besides previously identified pathways, we have identified new pathways and genes that could be relevant for prevention and intervention studies of subcutaneous radiation-induced fibrosis as well as being candidates for SNP association studies.
Rødningen
Olaug Kristin
OK
Department of Genetics, Institute of Cancer Research, Faculty Division, The Norwegian Radium Hospital, University of Oslo, Norway. olaug.rodningen@klinmed.uio.no
Overgaard
Jens
J
Alsner
Jan
J
Hastie
Trevor
T
Børresen-Dale
Anne-Lise
AL
D001943:Breast Neoplasms / Q000473:pathology / Q000532:radiotherapy; D018929:Cell Culture Techniques; D002453:Cell Cycle / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D005260:Female; D005347:Fibroblasts / Q000502:physiology* / Q000528:radiation effects*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D017564:Radiation Pneumonitis / Q000503:physiopathology*; D011839:Radiation, Ionizing; D015398:Signal Transduction; D014158:Transcription, Genetic; D051153:Wnt Proteins / Q000096:biosynthesis / Q000502:physiology
D051153:Wnt Proteins