Regulation of Cyclooxygenase-2 and Periostin by Wnt-3 in Mouse Mammary Epithelial Cells

Abstract

Wnt family members are critical in developmental processes and have been shown to promote carcinogenesis when ectopically expressed in the mouse mammary gland. The gene expression pattern mediated by Wnt is pivotal for these diverse responses. The Wnt pathway has been conserved among different species. Genetic studies have shown that Wnt effects are mediated, at least in part, by ␤-catenin, which regulates transcription of "downstream genes." Wnt stimulation inactivates glycogen-synthase kinase-3␤ (GSK-3) with subsequent stabilization of ␤-catenin, which after heterodimerizing with lymphocyte enhancer factor-1/T-cell factor cofactors stimulates transcription. To establish whether Wntstimulated transcription is mediated solely by ␤-catenin, a comparison was made of gene expression profiles in response to Wnt-3, overexpression of ␤-catenin, and inhibition of GSK-3. Infection of cells with Wnt-3 and inhibition of GSK-3 regulate a set of genes that include cyclooxygenase-2 and periostin. Interestingly, overexpression of ␤-catenin or reducing ␤-catenin levels with antisense oligonucleotide transfection did not have any effect on cyclooxygenase-2 or periostin expression, thereby defining a Wnt pathway, which cannot be mimicked by ␤-catenin overexpression.

β-catenin is a downstream effector of Wnt-mediated tumorigenesis in the mammary gland

“…Of note, tumor development in females also has a longer latency in MMTV-bcatDN mice as compared to those in the MMTV-Wnt models. Intriguingly, the di erence could potentially be attributed to b-catenin-independent Wnt signaling (Haertel-Wiesmann et al, 2000;Ziemer et al, 2001) which may activate pathways the consequence of which is an acceleration of the rate of oncogenesis. The role of alternate downstream components of the Wnt pathway in mammary tumorigenesis therefore cannot be ruled out.…”

Role of alternative splicing of periostin in human bladder carcinogenesis

“…ßig-h3 promotes cell adhesion and fibroblast spreading via integrin α1ß2 (8,9) and suppresses the ability of Chinese hamster ovary (CHO) cells to develop into tumors in nude mice (10). The expression of periostin is also increased by TGF-ß (1), and periostin mRNA expression is down-regulated by the introduction of Wnt-3 and by the inhibition of glycogen synthase kinase 3ß (GSK-3ß) (11), suggesting that loss of periostin expression could promote oncogenesis. However, in most human tumors, including colon cancer (12), breast cancer (13), lung cancer (14), head and neck cancer (15), oral cancer (16) and pancreatic cancer (17), periostin expression has been shown to be up-regulated; however, this is not true of bladder cancer (18).…”

Cell autonomous regulation of multiple Dishevelled-dependent pathways by mammalian Nkd

“…Together, our findings that mNkd interacted directly with Dishevelled and inhibited the canonical Wnt pathway upstream of ␤-catenin suggest that mNkd is an intracellular antagonist of the Wnt pathway. (30)(31)(32)(33). We also tested whether mNkd-mRNA levels changed when cells were treated with Wnt ligands.…”