The role of LEF/TCF factors in neoplastic transformation.

The T cell factor 4 (Tcf-4) interacts with beta-catenin in the Wnt signalling pathway and coactivates downstream target genes in diverse systems including the breast. This activity is important during normal development but its deregulation plays a pivotal role in cancer progression. In a rat model for breast cancer it has been shown that metastasis-inducing DNA (Met-DNA) sequesters the endogenous inhibitory Tcf-4 and thereby promotes transcription of the secreted extracellular matrix glycophosphoprotein, osteopontin, the direct effector of metastasis in this model system. Permanent transfection of the benign rat mammary cell line with a fragment from the Met-DNA containing the Tcf recognition sequence CAAAG induces the cells to metastasize in syngeneic rats in vivo. Tcf-4 expression in human breast carcinomas is inversely associated with osteopontin protein levels. High Tcf-4 expression impedes both OPN promoter activity and protein expression in rat mammary carcinoma cells. Understanding the role of Tcf-4 in cancer development and its transcription regulation should lay the foundation for novel therapeutic approaches in the future.