Epigenetic silencing of the candidate tumor suppressor gene PROX1 in sporadic breast cancer.
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.
Versmold
Beatrix
B
Division of Molecular Gyneco-Oncology, Department of Gynecology and Obstetrics, University of Cologne, Germany.
Felsberg
Jörg
J
Mikeska
Thomas
T
Ehrentraut
Denise
D
Köhler
Juliane
J
Hampl
Juergen A
JA
Röhn
Gabriele
G
Niederacher
Dieter
D
Betz
Beate
B
Hellmich
Martin
M
Pietsch
Torsten
T
Schmutzler
Rita K
RK
Waha
Andreas
A
D000328:Adult; D000368:Aged; D001374:Azacitidine / Q000494:pharmacology; D001932:Brain Neoplasms / Q000556:secondary; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D000098551:Prospero-Related Homeobox 1 Protein
D004273:DNA, Neoplasm; D018398:Homeodomain Proteins; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein; D001374:Azacitidine