β-catenin–sensitive isoforms of lymphoid enhancer factor-1 are selectively expressed in colon cancer

Abstract

Constitutive activation of the Wnt signaling pathway is a root cause of many colon cancers. Activation of this pathway is caused by genetic mutations that stabilize the beta-catenin protein, allowing it to accumulate in the nucleus and form complexes with any member of the lymphoid enhancer factor (LEF1) and T-cell factor (TCF1, TCF3, TCF4) family of transcription factors (referred to collectively as LEF/TCFs) to activate transcription of target genes. Target genes such as MYC, CCND1, MMP7 and TCF7 (refs. 5-9) are normally expressed in colon tissue, so it has been proposed that abnormal expression levels or patterns imposed by beta-catenin/TCF complexes have a role in tumor progression. We report here that LEF1 is a new type of target gene ectopically activated in colon cancer. The pattern of this ectopic expression is unusual because it derives from selective activation of a promoter for a full-length LEF1 isoform that binds beta-catenin, but not a second, intronic promoter that drives expression of a dominant-negative isoform. beta-catenin/TCF complexes can activate the promoter for full-length LEF1, indicating that in cancer high levels of these complexes misregulate transcription to favor a positive feedback loop for Wnt signaling by inducing selective expression of full-length, beta-catenin-sensitive forms of LEF/TCFs.

Frequent epigenetic inactivation of SFRP genes and constitutive activation of Wnt signaling in gastric cancer

“…LEF1 (Hovanes et al, 2001), MMP7 (Brabletz et al, 1999), cyclin D1 (Tetsu and McCormick, 1999) and CD44 (Wielenga et al, 1999) are all reported to be direct or indirect targets of b-catenin-TCF/LEF, confirming that Wnt signaling is blocked by SFRP2 in SNU638 cells (Table 2). We also found that significant numbers of genes related to cellular proliferation, growth or apoptosis are repressed or induced by SFRP2.…”

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

“…Wnt signaling regulates various developmental processes and can lead to cancer formation. MMP7 has been reported overexpressed in human gastric cancers Yamamoto et al, 2004) and colorectal cancers (Matsushima et al, 1998;Hovanes et al, 2001). Recently, Chung et al conducted an IHC analysis of regulation of the b-catenin signaling pathway on a breast cancer tissue microarray.…”

Gastrin stabilises β-catenin protein in mouse colorectal cancer cells

“…A recent study has suggested the existence of another pathological vicious cycle involving b-catenin in CRC. In addition to its effects on gastrin and on the expression of other target genes, Hovanes et al (2001) reported that LEF-1, one of the transcriptional partners of bcatenin, is likewise a target gene of b-catenin/TCF-dependent transcription.…”