Role of β-Catenin/T-Cell Factor-Regulated Genes in Ovarian Endometrioid Adenocarcinomas

Abstract

In various cancers, inactivating mutations in the adenomatous polyposis coli or Axin tumor suppressor proteins or activating mutations in beta-catenin's amino-terminal domain elevate beta-catenin levels, resulting in marked effects on T-cell factor (TCF)-regulated transcription. Several candidate beta-catenin/TCF-regulated genes in cancer have been proposed. Expression of a few of these genes has been studied in primary human cancers, but most studies have focused on colon cancers and not on other cancer types that harbor mutational defects in adenomatous polyposis coli, AXIN, or beta-catenin. Mutations leading to beta-catenin deregulation are found in nearly half of ovarian endometrioid adenocarcinomas (OEAs). We report here on the expression of 6 candidate beta-catenin/TCF-regulated genes in a panel of 44 primary OEAs, more than a third of which carry demonstrable defects in beta-catenin regulation. Using quantitative assays of gene expression, we found significantly elevated expression of the MMP-7, CCND1 (Cyclin D1), CX43 (Connexin 43), PPAR-delta, and ITF2 genes in OEAs with deregulated beta-catenin. This correlation was not observed for c-myc, another putative beta-catenin/TCF-regulated gene. Immunohistochemical studies confirmed that overexpression of cyclin D1 and MMP-7 was highly associated with nuclear accumulation of beta-catenin and mutational defects of the Wnt/beta-catenin/TCF-signaling pathway. Our findings indicate cyclin D1, MMP-7, connexin 43, PPAR-delta, and ITF-2, likely play important roles in the pathogenesis of those OEAs that manifest defects in beta-catenin regulation.

Prognostic significance of matrix metalloproteinase‐7 in epithelial ovarian cancer and its relation to β‐catenin expression

“…20 Interestingly, high MMP-7 and intense MMP-7 expression in tumor cells is also related to strong cyto- 17 While MMP-7 thus appears to be a target gene for b-catenin/TCF complex in epithelial ovarian cancer, there are also other factors that regulate MMP-7 production. 18 The present study appears to be the first report on the association of MMP-7 with standard prognostic factors and patient survival in ovarian cancer, with the interesting notion that a low percentage area of MMP-7 expression or low percentage area of intense MMP-7 expression in tumor cells correlates with a poor differentiation and advanced stage of the tumor, large primary residual tumor and a poor prognosis in general. Similarly, in nonendometrioid cancers, a low expression of MMP-7 correlates with grade 3 tumors.…”

Transcriptional profiling suggests that Barrett's metaplasia is an early intermediate stage in esophageal adenocarcinogenesis

“…MMP7 has been considered a target in the Wnt signal pathway (Zhai et al, 2002;Schwartz et al, 2003). Wnt signaling regulates various developmental processes and can lead to cancer formation.…”

Low membranous expression of β-catenin and high mitotic count predict poor prognosis in endometrioid carcinoma of the ovary

“…b-catenin gene mutations are common molecular alterations in endometrioid carcinomas and therefore have emerged as a promising prognostic marker of this tumor. [11][12][13][14][15] b-Catenin has been implicated in two important biological processes: cell-cell adhesion and signal transduction. 16 In adherens junctions of epithelial cells, b-catenin association with the cytoplasmic domain of cadherins has an important function in Ca 2 þ -dependent cell adhesion.…”