期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2020227118
关键词
beta-catenin; breast cancer; cell adhesion; metastasis; Wnt signaling
资金
- Swiss NSF [310030B_163471, 310030B_173331]
- Swiss NSF Sinergia Grant
- Swiss Cancer League [KFS-3479-08-2014]
- Krebsliga Beider Basel [03-2013]
- Swiss National Science Foundation (SNF) [310030B_163471, 310030B_173331] Funding Source: Swiss National Science Foundation (SNF)
The transcriptional activity of beta-catenin plays a crucial role in the malignant progression of breast cancer, affecting tumor growth, invasion, and metastasis formation. This contrasts its adhesion function, highlighting the importance of Wnt/beta-catenin-dependent transcription in cancer progression.
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 Bd9 and Pygo-pus, 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.
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