PMID- 34408016 OWN - NLM STAT- MEDLINE DCOM- 20211213 LR - 20220219 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 118 IP - 34 DP - 2021 Aug 24 TI - Parsing beta-catenin's cell adhesion and Wnt signaling functions in malignant mammary tumor progression. LID - 10.1073/pnas.2020227118 [doi] LID - e2020227118 AB - During malignant progression, epithelial cancer cells dissolve their cell-cell adhesion and gain invasive features. By virtue of its dual function, beta-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 beta-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 beta-catenin with the specific ablation of its signaling outputs in mammary tumor cells. Notably, the complete lack of beta-catenin resulted in massive apoptosis of mammary tumor cells. In contrast, the loss of beta-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 beta-catenin's transcriptional activities upon stimulation with Wnt3a or during TGF-beta-induced EMT. Our results uncouple the signaling from the adhesion function of beta-catenin and underline the importance of Wnt/beta-catenin-dependent transcription in malignant tumor progression of breast cancer. FAU - Buechel, David AU - Buechel D AD - Department of Biomedicine, University of Basel, 4031 Basel, Switzerland. FAU - Sugiyama, Nami AU - Sugiyama N AUID- ORCID: 0000-0003-0788-2934 AD - Department of Biomedicine, University of Basel, 4031 Basel, Switzerland. FAU - Rubinstein, Natalia AU - Rubinstein N AUID- ORCID: 0000-0002-5690-1516 AD - Instituto de Biociencias, Biotecnologia y Biologia Traslacional, Departamento de Fisiologia, Biologia Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, 2160 Buenos Aires, Argentina. FAU - Saxena, Meera AU - Saxena M AUID- ORCID: 0000-0002-4060-4218 AD - Department of Biomedicine, University of Basel, 4031 Basel, Switzerland. FAU - Kalathur, Ravi K R AU - Kalathur RKR AD - Department of Biomedicine, University of Basel, 4031 Basel, Switzerland. AD - Murdoch Children's Research Institute, Royal Children's Hospital, Parkville VIC 3052, Australia. FAU - Luond, Fabiana AU - Luond F AD - Department of Biomedicine, University of Basel, 4031 Basel, Switzerland. FAU - Vafaizadeh, Vida AU - Vafaizadeh V AUID- ORCID: 0000-0002-0875-6246 AD - Department of Biomedicine, University of Basel, 4031 Basel, Switzerland. FAU - Valenta, Tomas AU - Valenta T AUID- ORCID: 0000-0002-3043-1835 AD - Department of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland. FAU - Hausmann, George AU - Hausmann G AUID- ORCID: 0000-0002-2146-6665 AD - Department of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland. FAU - Cantu, Claudio AU - Cantu C AUID- ORCID: 0000-0003-1547-5415 AD - Wallenberg Centre for Molecular Medicine, Linkoping University, 581 83 Linkoping, Sweden. AD - Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology, Faculty of Medicine and Health Sciences, Linkoping University, 581 83 Linkoping, Sweden. FAU - Basler, Konrad AU - Basler K AUID- ORCID: 0000-0003-3534-1529 AD - Department of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland. FAU - Christofori, Gerhard AU - Christofori G AUID- ORCID: 0000-0002-8696-9896 AD - Department of Biomedicine, University of Basel, 4031 Basel, Switzerland; gerhard.christofori@unibas.ch. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Transforming Growth Factor beta) RN - 0 (Wnt3A Protein) RN - 0 (Wnt3a protein, mouse) RN - 0 (beta Catenin) SB - IM MH - Animals MH - Apoptosis MH - Cell Adhesion/*physiology MH - Cell Cycle MH - Cell Movement MH - Epithelial-Mesenchymal Transition/drug effects MH - Female MH - Gene Expression Regulation, Neoplastic/drug effects MH - Mammary Neoplasms, Animal/genetics/*metabolism MH - Mice MH - Mice, Transgenic MH - Neoplasm Invasiveness MH - Neoplasm Metastasis MH - Signal Transduction/*physiology MH - Transcriptome MH - Transforming Growth Factor beta/pharmacology MH - Wnt3A Protein/genetics/*metabolism MH - beta Catenin/genetics/*metabolism PMC - PMC8403962 OTO - NOTNLM OT - Wnt signaling OT - breast cancer OT - cell adhesion OT - metastasis OT - beta-catenin COIS- The authors declare no competing interest. EDAT- 2021/08/20 06:00 MHDA- 2021/12/15 06:00 PMCR- 2022/02/18 CRDT- 2021/08/19 05:55 PHST- 2021/08/19 05:55 [entrez] PHST- 2021/08/20 06:00 [pubmed] PHST- 2021/12/15 06:00 [medline] PHST- 2022/02/18 00:00 [pmc-release] AID - 2020227118 [pii] AID - 202020227 [pii] AID - 10.1073/pnas.2020227118 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2021 Aug 24;118(34):e2020227118. doi: 10.1073/pnas.2020227118.