Bcl-3 promotes multi-modal tumour cell migration via NF-κB1 mediated regulation of Cdc42

Turnham, Daniel J; Yang, William W; Davies, Julia; Varnava, Athina; Ridley, Anne J; Conlan, R Steven; Clarkson, Richard W E

Abstract

A key challenge in the implementation of anti-metastatics as cancer therapies is the multi-modal nature of cell migration, which allows tumour cells to evade the targeted inhibition of specific cell motility pathways. The nuclear factor-kappaB (NF-κB) co-factor B-cell lymphoma 3 (Bcl-3) has been implicated in breast cancer cell migration and metastasis, yet it remains to be determined exactly which cell motility pathways are controlled by Bcl-3 and whether migrating tumour cells are able to evade Bcl-3 intervention. Addressing these questions and the mechanism underpinning Bcl-3’s role in this process would help determine its potential as a therapeutic target. Here we identify Bcl-3 as an upstream regulator of the two principal forms of breast cancer cell motility, involving collective and single-cell migration. This was found to be mediated by the master regulator Cdc42 through binding of the NF-κB transcription factor p50 to the Cdc42 promoter. Notably, Bcl-3 depletion inhibited both stable and transitory motility phenotypes in breast cancer cells with no evidence of migratory adaptation. Overexpression of Bcl-3 enhanced migration and increased metastatic tumour burden of breast cancer cells in vivo, whereas overexpression of a mutant Bcl-3 protein, which is unable to bind p50, suppressed cell migration and metastatic tumour burden suggesting that disruption of Bcl-3/NF-κB complexes is sufficient to inhibit metastasis. These findings identify a novel role for Bcl-3 in intrinsic and adaptive multi-modal cell migration mediated by its direct regulation of the Rho GTPase Cdc42 and identify the upstream Bcl-3:p50 transcription complex as a potential therapeutic target for metastatic disease.

• Journal Article Type: Article
• Acceptance Date: Jan 15, 2020
• Online Publication Date: Jan 20, 2020
• Publication Date: Oct 15, 2020
• Deposit Date: Oct 22, 2024
• Publicly Available Date: Oct 29, 2024
• Journal: Carcinogenesis
• Print ISSN: 0143-3334
• Electronic ISSN: 1460-2180
• Publisher: Oxford University Press (OUP)
• Peer Reviewed: Peer Reviewed
• Volume: 41
• Issue: 10
• Pages: 1432-1443
• DOI: https://doi.org/10.1093/carcin/bgaa005
• Public URL: https://uwe-repository.worktribe.com/output/13307594