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

✍ Scribed by Beatrix Versmold; Jörg Felsberg; Thomas Mikeska; Denise Ehrentraut; Juliane Köhler; Juergen A. Hampl; Gabriele Röhn; Dieter Niederacher; Beate Betz; Martin Hellmich; Torsten Pietsch; Rita K. Schmutzler; Andreas Waha

Publisher
John Wiley and Sons
Year
2007
Tongue
French
Weight
362 KB
Volume
121
Category
Article
ISSN
0020-7136

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✦ Synopsis

Abstract

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. © 2007 Wiley‐Liss, Inc.

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