Parsing β-catenin?s cell adhesion and Wnt signaling functions in malignant mammary tumor progression

DAVID BUECHEL; NATALIA RUBINSTEIN.; NAMI SUGIYAMA; MEERA SAXENA; RAVI K. KALATHUR; LÜÖND FABIANA; VAFAIZADEH VIDA; VALENTA TOMAS; HAUSMANN GEORGE; CLAUDIO CANTU; KONRAD BASLER; GERHARD CHRISTOFORI

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

NATL ACAD SCIENCES

Lugar: Washington DC, USA; Año: 2021

0027-8424

During malignant progression, epithelial cancer cells dissolve their cell-cell adhesion and gain͵ͷ invasive features. By virtue of its dual function, E-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͵ͺ general transcriptional machinery. This duality confounds the simple loss of function analysis of͵ͻ Wnt signaling in cancer progression. In many cancer types including breast cancer, the functionalͶͲ contribution of E-catenin?s transcriptional activities, as compared to its adhesion functions, toͶͳ tumor progression has remained elusive. Employing the MMTV-PyMT mouse model ofͶʹ metastatic breast cancer we compared the complete elimination of E-catenin with the specificͶ͵ ablation of its signaling outputs in mammary tumor cells. Notably, the complete lack of β-cateninͶͶ resulted in massive apoptosis of mammary tumor cells. In contrast, the loss of β-catenin?sͶͷ transcriptional activity resulted in a reduction of primary tumor growth, tumor invasion, andͶ͸ metastasis formation in vivo. These phenotypic changes were reflected by stalled cell cycleͶ͹ progression and diminished epithelial-mesenchymal transition (EMT) and cell migration of breastͶͺ cancer cells in vitro. Transcriptome analysis revealed subsets of genes which were specificallyͶͻ regulated by β-catenin?s transcriptional activities upon stimulation with Wnt3a or during TGFEͷͲ induced EMT. Our results uncouple the signaling from the adhesion function of E-catenin, andͷͳ underline the importance of Wnt/E-catenin-dependent transcription in malignant tumorͷʹ progression of breast cancer.