1. The interactions of Bcl9/Bcl9L with β-catenin and Pygopus promote breast cancer growth, invasion, and metastasis
- Author
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Lorenzo Bazzani, David Buechel, Tomas Valenta, Vida Vafaizadeh, Natalia Rubinstein, Claudio Cantù, Meera Saxena, Konrad Basler, Gerhard Christofori, Ravi Kiran Reddy Kalathur, and George Hausmann
- Subjects
Cancer Research ,Epithelial-Mesenchymal Transition ,Breast Neoplasms ,Tumor initiation ,medicine.disease_cause ,Article ,Morphogen signalling ,Metastasis ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Breast cancer ,Cell Line, Tumor ,Genetics ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,Neoplasm Metastasis ,Cancer models ,Molecular Biology ,Wnt Signaling Pathway ,beta Catenin ,030304 developmental biology ,0303 health sciences ,Mammary tumor ,biology ,Wnt signaling pathway ,Intracellular Signaling Peptides and Proteins ,medicine.disease ,biology.organism_classification ,Primary tumor ,3. Good health ,DNA-Binding Proteins ,Tumor progression ,030220 oncology & carcinogenesis ,Cancer research ,Disease Progression ,Female ,Carcinogenesis ,Pygopus ,Neoplasm Transplantation ,Transcription Factors - Abstract
Canonical Wnt/β-catenin signaling is an established regulator of cellular state and its critical contributions to tumor initiation, malignant tumor progression and metastasis formation have been demonstrated in various cancer types. Here, we investigated how the binding of β-catenin to the transcriptional coactivators B-cell CLL/lymphoma 9 (Bcl9) and Bcl9-Like (Bcl9L) affected mammary gland carcinogenesis in the MMTV-PyMT transgenic mouse model of metastatic breast cancer. Conditional knockout of both Bcl9 and Bcl9L resulted into tumor cell death. In contrast, disrupting the interaction of Bcl9/Bcl9L with β-catenin, either by deletion of their HD2 domains or by a point mutation in the N-terminal domain of β-catenin (D164A), diminished primary tumor growth and tumor cell proliferation and reduced tumor cell invasion and lung metastasis. In comparison, the disruption of HD1 domain-mediated binding of Bcl9/Bcl9L to Pygopus had only moderate effects. Interestingly, interfering with the β-catenin-Bcl9/Bcl9L-Pygo chain of adapters only partially impaired the transcriptional response of mammary tumor cells to Wnt3a and TGFβ treatments. Together, the results indicate that Bcl9/Bcl9L modulate but are not critically required for canonical Wnt signaling in its contribution to breast cancer growth and malignant progression, a notion consistent with the “just-right” hypothesis of Wnt-driven tumor progression.
- Published
- 2021