Buechel, David, Sugiyama, Nami, Rubinstein, Natalia, Saxena, Meera, Kalathur, Ravi K R, Lüönd, Fabiana, Vafaizadeh, Vida, Valenta, Tomas, Hausmann, George, Cantù, Claudio, Basler, Konrad and Christofori, Gerhard (2021) Parsing β-catenin's cell adhesion and Wnt signaling functions in malignant mammary tumor progression. Proceedings of the National Academy of Sciences of the United States of America, 118 (34). ISSN 1091-6490

Abstract

During malignant progression, epithelial cancer cells dissolve their cell-cell adhesion and gain invasive features. By virtue of its dual function, β-catenin contributes to cadherin-mediated cell-cell adhesion, and it determines the transcriptional output of Wnt signaling: via its N terminus, it recruits the signaling coactivators Bcl9 and Pygopus, and via the C terminus, it interacts with the general transcriptional machinery. This duality confounds the simple loss-of-function analysis of Wnt signaling in cancer progression. In many cancer types including breast cancer, the functional contribution of β-catenin's transcriptional activities, as compared to its adhesion functions, to tumor progression has remained elusive. Employing the mouse mammary tumor virus (MMTV)-PyMT mouse model of metastatic breast cancer, we compared the complete elimination of β-catenin with the specific ablation of its signaling outputs in mammary tumor cells. Notably, the complete lack of β-catenin resulted in massive apoptosis of mammary tumor cells. In contrast, the loss of β-catenin's transcriptional activity resulted in a reduction of primary tumor growth, tumor invasion, and metastasis formation in vivo. These phenotypic changes were reflected by stalled cell cycle progression and diminished epithelial-mesenchymal transition (EMT) and cell migration of breast cancer cells in vitro. Transcriptome analysis revealed subsets of genes which were specifically regulated by β-catenin's transcriptional activities upon stimulation with Wnt3a or during TGF-β-induced EMT. Our results uncouple the signaling from the adhesion function of β-catenin and underline the importance of Wnt/β-catenin-dependent transcription in malignant tumor progression of breast cancer.

Item Type:	Article
Date Deposited:	19 Feb 2022 00:45
Last Modified:	19 Feb 2022 00:45
URI:	https://oak.novartis.com/id/eprint/46858