Blood gene expression profiling of breast cancer survivors experiencing fibrosis

Int J Radiat Oncol Biol Phys. 2011 Mar 1;79(3):875-83. doi: 10.1016/j.ijrobp.2010.09.052. Epub 2010 Dec 2.

Abstract

Purpose: 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 and materials: 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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast / pathology*
  • Breast / radiation effects
  • Breast Neoplasms / blood
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / radiotherapy
  • Down-Regulation
  • Female
  • Fibrosis
  • Gene Expression Profiling / methods*
  • Humans
  • Middle Aged
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Radiation Injuries / blood
  • Radiation Injuries / genetics*
  • Radiation Injuries / pathology
  • Radiotherapy, Adjuvant
  • Survivors
  • Time Factors
  • Transforming Growth Factor beta1 / genetics*
  • Transforming Growth Factor beta1 / metabolism
  • Up-Regulation

Substances

  • Plasminogen Activator Inhibitor 1
  • Transforming Growth Factor beta1