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.