Differential gene expression in ovarian tumors reveals Dusp 4 and Serpina 5 as key regulators for benign behavior of serous borderline tumors.
OBJECTIVE
Ovarian serous borderline tumors (SBT) are characterized by arborizing papillae lined by stratified epithelial cells, varying atypia, and absence of stromal invasion. Originally, these tumors have been classified as borderline because they behaved in a remarkably indolent manner, even with widespread tumor deposits called implants and the presence of lymph node involvement. The molecular biology of these lesions has just begun to be explored. High prevalence of B-RAF/K-RAS mutations in SBTs in contrast to serous carcinomas (SCAs) indicates that the mitogenic RAS-RAF-MEK-ERK-MAP kinase pathway is crucial for the pathogenesis of SBTs. The purpose of this study was to further unravel the genetic pathways through which SBTs develop, with a special focus on explaining the generally benign SBT behavior.


METHODS
We generated RNA expression profiles of 38 ovarian serous neoplasms. Global Test pathway analysis and significance analysis of microarrays (SAM) of the expression profiles was performed.


RESULTS
SAM and Global Testing showed that although the mitogenic pathway is activated in SBTs, activation of downstream genes involved in extracellular matrix (ECM) degradation is absent, suggesting an uncoupling of both events. In addition, we show that two genes involved in regulating this uncoupling, ERK-inhibitor Dusp 4 and uPA-inhibitor Serpina 5, are downregulated in SCAs in contrast to SBTs. In SCAs, this was associated with downstream MMP-9 activation at both mRNA and protein level.


CONCLUSIONS
We propose that the putative tumor suppressor genes Dusp 4 and Serpina 5 provide a major clue to the indolent behavior of SBTs.
Sieben
Nathalie L G
NL
Department of Pathology, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, the Netherlands. nathalie.sieben@path.unimaas.nl
Oosting
Jan
J
Flanagan
Adrienne M
AM
Prat
Jaime
J
Roemen
Guido M J M
GM
Kolkman-Uljee
Sandra M
SM
van Eijk
Ronald
R
Cornelisse
Cees J
CJ
Fleuren
Gert Jan
GJ
van Engeland
Manon
M
D054637:Dual-Specificity Phosphatases; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D016147:Genes, Tumor Suppressor; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D054639:Mitogen-Activated Protein Kinase Phosphatases; D009154:Mutation; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics*; D018046:Protein C Inhibitor / Q000235:genetics*; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics
D018046:Protein C Inhibitor; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D054639:Mitogen-Activated Protein Kinase Phosphatases; C490583:DUSP4 protein, human; D054637:Dual-Specificity Phosphatases; D017027:Protein Tyrosine Phosphatases; D020780:Matrix Metalloproteinase 9