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

VAFAIZADEH VIDA; DAVID BUECHEL; NATALIA RUBINSTEIN.; RAVI K. KALATHUR; BAZZANI L; MEERA SAXENA; TOMAS VALENTA; HAUSMANN GEORGE; CLAUDIO CANTU; KONRAD BASLER; GERHARD CHRISTOFORI

ONCOGENE

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2021

0950-9232

High cell plasticity is a hallmark of metastatic cancer cells. Canonical Wnt/β-catenin signaling is well established as a regulatory pathway of cellular state, however, how its contribution to cell plasticity and metastasis is poorly understood. Here, we investigated the dependence of -catenin to bind to the transcriptional coactivators B-cell CLL/lymphoma 9 (Bcl9) and Bcl9-Like (Bcl9L) during mammary gland carcinogenesis in the MMTV-PyMT transgenic mouse model of metastatic breast cancer. Conditional knockout of both Bcl9 and Bcl9L genes affected cell survival but not tumor progression. In contrast, disrupting the interaction of Bcl9/Bcl9L with -catenin, either by deletion of their HD2 domains or by a point mutation in the N-terminal domain of -catenin (D164A), diminished primary tumor growth and tumor cell proliferation and reduced tumor cell invasion and lung metastasis. In comparison, this effect was moderate when binding of Bcl9/Bcl9L to Pygopus was disrupted by deletion of their HD1 domains. Cells lacking the Bcl9/Bcl9L - -catenin interactions were only partially impaired in responding to Wnt3a and to TGF, yet with a significant change in the expression of Wnt3a and TGF target genes. The results indicate that Bcl9/Bcl9L critically enforce canonical Wnt signaling in its contribution to breast cancer growth and malignant progression