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

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

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1432-1443
Number of pages12
Issue number10
StatePublished - Oct 1 2020

ASJC Scopus subject areas

  • Cancer Research


Dive into the research topics of 'Bcl-3 promotes multi-modal tumour cell migration via NF-κB1 mediated regulation of Cdc42'. Together they form a unique fingerprint.

Cite this