Blood gene expression profiling of breast cancer survivors experiencing fibrosis.
OBJECTIVE
To extend knowledge on the mechanisms and pathways involved in maintenance of radiation-induced fibrosis (RIF) by performing gene expression profiling of whole blood from breast cancer (BC) survivors with and without fibrosis 3-7 years after end of radiotherapy treatment.


METHODS
Gene expression profiles from blood were obtained for 254 BC survivors derived from a cohort of survivors, treated with adjuvant radiotherapy for breast cancer 3-7 years earlier. Analyses of transcriptional differences in blood gene expression between BC survivors with fibrosis (n=31) and BC survivors without fibrosis (n=223) were performed using R version 2.8.0 and tools from the Bioconductor project. Gene sets extracted through a literature search on fibrosis and breast cancer were subsequently used in gene set enrichment analysis.


RESULTS
Substantial differences in blood gene expression between BC survivors with and without fibrosis were observed, and 87 differentially expressed genes were identified through linear analysis. Transforming growth factor-β1 signaling was identified as the most significant gene set, showing a down-regulation of most of the core genes, together with up-regulation of a transcriptional activator of the inhibitor of fibrinolysis, Plasminogen activator inhibitor 1 in the BC survivors with fibrosis.


CONCLUSIONS
Transforming growth factor-β1 signaling was found down-regulated during the maintenance phase of fibrosis as opposed to the up-regulation reported during the early, initiating phase of fibrosis. Hence, once the fibrotic tissue has developed, the maintenance phase might rather involve a deregulation of fibrinolysis and altered degradation of extracellular matrix components.
Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Institute for Clinical Medicine, University of Oslo, Oslo, Norway. hblandma@rr-research.no
Hege
H
Landmark-Høyvik
Vanessa
V
Dumeaux
Kristin V
KV
Reinertsen
Hege
H
Edvardsen
Sophie D
SD
Fosså
Anne-Lise
AL
Børresen-Dale
D001940:Breast / Q000473:pathology* / Q000528:radiation effects; D001943:Breast Neoplasms / Q000097:blood / Q000235:genetics* / Q000532:radiotherapy; D015536:Down-Regulation; D005260:Female; D005355:Fibrosis; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011832:Radiation Injuries / Q000097:blood / Q000235:genetics* / Q000473:pathology; D018714:Radiotherapy, Adjuvant; D017741:Survivors; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
D017395:Plasminogen Activator Inhibitor 1; D053773:Transforming Growth Factor beta1