The interactions of Bcl9/Bcl9L with \u03b2-catenin and Pygopus promote breast cancer growth, invasion, and metastasis

Vida Vafaizadeh,Gerhard Christofori,Natalia Rubinstein,Meera Saxena,Konrad Basler,David Buechel,Tomas Valenta,Claudio Cantù,Ravi K R Kalathur,George Hausmann,Lorenzo Bazzani

doi:10.1038/s41388-021-02016-9

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.

Highlights

Aberrant canonical Wnt signaling and the resulting dysregulation of β-catenin’s transcriptional functions play key roles in the progression of inflammation, fibrosis, and tumor formation [1, 2]
We have found that the disruption of the interaction of β-catenin with B-cell CLL/lymphoma 9 (Bcl9)/Bcl9L proteins in tumor cells of MMTV-PyMT transgenic mice causes a significant reduction in primary tumor growth and metastasis formation
Wnt/β-catenin signaling is activated during TGFβ-induced epithelial–mesenchymal transition (EMT) We have previously induced EMT and mesenchymal–epithelial transition (MET) in the Py2T and 1099PyMT murine breast cancer cell lines derived from tumors of MMTV-PyMT transgenic mice and performed RNA-sequencing [26, 27, 29]

Summary

Introduction

Aberrant canonical Wnt signaling and the resulting dysregulation of β-catenin’s transcriptional functions play key roles in the progression of inflammation, fibrosis, and tumor formation [1, 2]. Β-catenin has two roles: it is a critical component of cadherinmediated cell–cell adhesion complexes and it is the transcriptional co-activator in canonical Wnt signaling. While the functional contribution of TGFβ signaling to EMT, malignant tumor progression, and metastasis formation has been amply demonstrated, the role of Wnt signaling in late-stage breast cancer progression still remains unclear. HD1 and HD2 are evolutionarily conserved domains that in mice are required for embryonic development; their individual disruption is lethal [13]

Methods

Results

Conclusion