Publications & Reports

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

Beatrix Versmold, Jorg Felsberg, Thomas Mikeska, Denise Ehrentraut, Juliane Kohler, Juergen A Hampl, Gabriele Rohn, Dieter Niederacher, Beate Betz, Martin Hellmich, Torsten Pietsch, Rita K Schmutzler, Andreas Waha
Division of Molecular Gyneco-Oncology, Department of Gynecology and Obstetrics, University of Cologne, Germany.


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.


  • Journal: International Journal of Cancer
  • Published: 01/08/2007
  • Volume: 121
  • Issue: 3
  • Pagination: 547-554