β-Catenin and Tcfs in Mammary Development and Cancer

Sarah Hatsell, New York University School of Medicine
Tracey Rowlands, New York University School of Medicine
Minoti Hiremath, New York University School of Medicine
Pamela Cowin, New York University School of Medicine

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 N89 β-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.