Epigenetic silencing of the candidate tumor suppressor gene PROX1 in sporadic breast cancer

Int J Cancer. 2007 Aug 1;121(3):547-54. doi: 10.1002/ijc.22705.


Extensive hypermethylation and consecutive transcriptional silencing of tumorsuppressor genes have been documented in multiple tumor entities including breast cancer. In a microarray based genome-wide methylation analysis of five sporadic breast carcinomas we identified a hypermethylated CpG island within the first intron of the prospero related homeobox gene 1 (PROX1). We, therefore, investigated CpG island methylation of PROX1 in a series of 33 pairs of primary breast cancer and corresponding normal tissue samples by bisulfite sequencing and COBRA analyses. Seventeen of these (52%) breast cancer samples revealed a significant accumulation of methylated CpG sites along with a significant reduction of PROX1 transcription compared to normal breast tissues of the same patients. Frequent methylation was also observed in brain metastases from primary breast cancer (21/37 = 57% of cases). Secondary, we analysed 38 brain metastases of primary breast carcinomas and detected a significantly reduced expression of PROX1 compared to normal breast tissue (p < 0.001) and primary breast carcinomas (p < 0.05), respectively. Additionally, treatment of breast cancer cell lines with demethylating agents could reactivate PROX1 transcription. In summary, we have identified PROX1 as a novel target gene that is hypermethylated and transcriptionally silenced in primary and metastatic breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Azacitidine / pharmacology
  • Brain Neoplasms / secondary
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • CpG Islands
  • DNA Methylation*
  • DNA, Neoplasm / metabolism
  • Epigenesis, Genetic*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing*
  • Genes, Tumor Suppressor
  • Homeodomain Proteins / genetics*
  • Humans
  • Middle Aged
  • Oligonucleotide Array Sequence Analysis
  • Transcription, Genetic
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins / genetics*


  • DNA, Neoplasm
  • Homeodomain Proteins
  • Tumor Suppressor Proteins
  • prospero-related homeobox 1 protein
  • Azacitidine