β -Catenin and Tcfs in Mammary Development and Cancer

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Abstract
β-Catenin regulates cell–cell adhesion and transduces signals from many pathways to regulate the transcriptional activities of Tcf/Lef DNA binding factors. Gene ablation and transgenic expression studies strongly support the concept that β-catenin together with Lef/Tcf factors act as a switch to determine cell fate and promote cell survival and proliferation at several stages during mammary gland development. Mice expressing the negative regulator of Wnt/β-catenin signaling (K14-Dkk) fail to form mammary buds, and those lacking Lef-1 show an early arrest in this process at stage E13.5. Stabilized ΔN89β-catenin initiates precocious alveologenesis during pubertal development, and negative regulators of endogenous β-catenin signaling suppress normal alveologenesis during pregnancy. Stabilized β-catenin induces hyperplasia and mammary tumors in mice. Each of the β-catenin-induced phenotypes is accompanied by upregulation of the target genes cyclin D1 and c-myc. Cyclin D1, however, is dispensable for tumor formation and the initiation of alveologenesis but is essential for later alveolar expansion.