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

Constitutive activation of the Wnt signaling pathway is a root cause of many colon cancers(1-3). 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(3,4). 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.