beta-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 man y colon cancers(1-3). Activation of this pathway is caused by genetic mutat ions that stabilize the beta -catenin protein, allowing it to accumulate in the nucleus and form complexes with any member of the lymphoid enhancer fa ctor (LEF1) and T-cell factor (TCF1, TCF3, TCF4) family of transcription fa ctors (referred to collectively as LEF/TCFs) to activate transcription of t arget 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 abno rmal expression levels or patterns imposed by beta -catenin/TCF complexes h ave 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 ecto pic 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 i soform. beta -catenin/TCF complexes can activate the promoter for full-leng th LEF1, indicating that in cancer high levels of these complexes misregula te transcription to favor a positive feedback loop for Wnt signaling by ind ucing selective expression of full-length, beta -catenin-sensitive forms of LEF/TCFs.