期刊
ONCOGENE
卷 40, 期 43, 页码 6195-6209出版社
SPRINGERNATURE
DOI: 10.1038/s41388-021-02016-9
关键词
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资金
- SystemsX.ch MTD project MetastasiX [2014/268]
- Swiss National Science Foundation [310030B_163471]
- Swiss National Science Foundation Sinergia [CRSII3_136274]
- Knut and Alice Wallenberg Foundation
- Cancerfonden [CAN 2018/542]
- Universitat Basel (Universitatsbibliothek Basel)
- Swiss National Science Foundation (SNF) [310030B_163471, CRSII3_136274] Funding Source: Swiss National Science Foundation (SNF)
Canonical Wnt/β-catenin signaling plays a significant role in tumor initiation, progression, and metastasis in various cancer types. However, the binding of beta-catenin to Bcl9/Bcl9L is found to modulate rather than critically required for breast cancer growth and malignant progression. Interfering with the interaction between these proteins can reduce tumor growth and metastasis.
Canonical Wnt/beta-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 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 disruption of HD1 domain-mediated binding of Bcl9/Bcl9L to Pygopus had only moderate effects. Interestingly, interfering with the beta-catenin-Bcl9/Bcl9L-Pygo chain of adapters only partially impaired the transcriptional response of mammary tumor cells to Wnt3a and TGF beta 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.
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