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Abstract

Beta-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 beta-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/beta-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 deltaN89beta-catenin initiates precocious alveologenesis during pubertal development, and negative regulators of endogenous beta-catenin signaling suppress normal alveologenesis during pregnancy. Stabilized beta-catenin induces hyperplasia and mammary tumors in mice. Each of the beta-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.

Estrogen receptor positivity in mammary tumors of Wnt-1 transgenic mice is influenced by collaborating oncogenic mutations

“…The best studied, the so-called 'canonical' pathway, leads to stabilization of b-catenin, which in turn forms heterodimers with members of the LEF/TCF family of DNA binding proteins and transactivates a number of transcriptional targets, including c-Myc and Cyclin D1 (Hatsell et al, 2003;Nusse, 2003;Brennan and Brown, 2004). However, to our surprise, neither ER nor PR was detected in tumors from mice TG for bcatenin or c-Myc (Figure 1a).…”

“…However, to our surprise, neither ER nor PR was detected in tumors from mice TG for bcatenin or c-Myc (Figure 1a). The Wnt-1 induction of ER þ tumors, possibly through regulating progenitor cell self-renewal and multilineage differentiation, may require paracrine Wnt signaling or b-catenin-independent noncanonical Wnt signaling through Rho, JNK and PKC (Hatsell et al, 2003). However, we cannot exclude the possibility that the tumors in b-catenin TG mice arose from a slightly different (probably more differentiated) population of mammary cells due to the use of a different TG promoter .…”

“…As a result, b-catenin is stabilized, translocates to the nucleus and transactivates different genes depending on cellular context. Genes encoding components and transcriptional targets of the Wnt signaling pathway are mutated or deregulated in several types of human tumors including breast cancers (Ugolini et al, 2001;Hatsell et al, 2003;Bafico et al, 2004;Brennan and Brown, 2004;Klopocki et al, 2004;Milovanovic et al, 2004).…”

Atherosclerotic Calcification: Wnt Is the Hint

“…This results in the polyubiquitination and proteasomal degradation of β‐catenin 75, 76. In active Wnt signaling, Wnt binds Frizzled receptors and low‐density lipoprotein receptor–related protein (LRP) 5/6 coreceptors, resulting in the activation of Disheveled, which inhibits GSK3 activity and disrupts the adenomatous polyposis coli/Axin/GSK3 complex that targets β‐catenin for destruction 76, 77, 78. As a result, β‐catenin is stabilized, accumulates in the cytoplasm, and subsequently translocates to the nucleus 73.…”

P53 levels determine outcome during β-catenin tumor initiation and metastasis in the mammary gland and male germ cells

“…In one capacity b-catenin participates as the effector molecule in the Wnt signal transduction pathway (reviewed in Polakis, 2000;Smalley and Dale, 2001;Hatsell et al, 2003). b-catenin levels are regulated in the cell by the APC/Axin/GSK3b complex (Behrens et al, 1998;Ikeda et al, 1998;Kishida et al, 1998).…”