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

Summary: We studied how the binding of beta-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 beta-catenin, either by deletion of their HD2 domains or by a point mutation in the N-terminal domain of beta-catenin (D164A), diminished primary tumor growth and tumor cell proliferation and reduced tumor cell invasion and lung metastasis. In comparison, the effect of disrupting the HD1 domain-mediated binding of Bcl9/Bcl9L to Pygopus was more moderate. Interfering with the beta-catenin - Bcl9/Bcl9L - Pygo chain of adaptors only partially impaired the transcriptional response of mammary tumor cells to Wnt3a and TGF-beta treatment. The results indicate that Bcl9/Bcl9L critically enforce canonical Wnt signaling in its contribution to breast cancer growth and malignant progression. RNA-Seq of tumor-derived primary epithelial cells with "B9/B9L deltaHD1/fl", "B9/B9L deltaHD1/-", "B9/B9L deltaHD2/fl" and "B9/B9L deltaHD2/-" genotypes treated with no, Wnt3a (3 days, 100ng/ml) or TGF-beta (4 days, 2ng/ml). RNA-Seq is performed in biological duplicates. rec = recombinant used for "B9/B9L deltaHD1/-" and "B9/B9L deltaHD2/-" genotypes.