The role of Wnt signaling pathway defects in the pathogenesis of ovarian endometrioid adenocarcinomas.

Abstract

Ovarian cancer is the most lethal gynecological malignancy and the fourth leading cause of cancer-related deaths in women in the United States. The canonical Wnt signaling pathway is a highly conserved signal transduction pathway that is deregulated in numerous tumor types. Wnt signaling is deregulated in approximately 40% of ovarian endometrioid adenocarcinomas (OEA), a common type of ovarian cancer. An important consequence of Wnt pathway activation is stabilization of beta-catenin leading to transcription of various target genes. Oligonucleotide microarrays were used to compare the gene expression profile of OEAs exhibiting Wnt pathway dysregulation to OEAs lacking Wnt/p-catenin pathway defects as a robust strategy to identify novel downstream target genes. Among the putative Wnt pathway target genes identified (&ge;2 fold upregulation, p&le;0.05), expression of fibroblast growth factor 9 (FGF9) was consistently upregulated (over six-fold) in primary OEAs with Wnt/beta-catenin pathway defects compared to OEAs lacking such defects. We demonstrated that FGF9 transcripts are upregulated in response to various modes of Wnt pathway stimulation in different cell types including ovarian cancer cells. Further, a role for FGF9 in several processes associated with cancer development and progression was determined. Our findings support the notion that FGF9 is a key factor contributing to the cancer phenotype of OEAs carrying Wnt/beta-catenin pathway defects. After generating a robust strategy for investigating the downstream effects of Wnt signaling on gene transcription in OEAs, we were interested in interrogating the interaction of Wnt signaling with other pathways commonly deregulated in OEAs. We examined 72 primary OEAs for mutation of key genes in several pathways known to be involved in ovarian cancer pathogenesis (<italic>CTNNB1 </italic>(beta-catenin), <italic>K-RAS, B-RAF, PTEN, PIK3CA,</italic> and <italic> p53</italic>). Analysis of these data revealed a statistically significant correlation between deregulation of the Wnt pathway and of PIK3CA/PTEN signaling. Subsequent studies by others in the Cho laboratory demonstrated that these pathways cooperate to promote transformation <italic>in vivo.</italic> These data support an important role for the Wnt/beta-cat and P13K/PTEN pathways individually, and suggest a unique role for combined deregulation of these pathways, in the pathogenesis of OEAs. Understanding the mechanisms of pathway interaction in OEAs will elucidate underlying molecular events that promote the development of ovarian cancers with endometrioid differentiation.