Bcl-3 promotes multi-modal tumour cell migration via NF-kB1 mediated regulation of Cdc42

Turnham, Daniel J. ORCID: https://orcid.org/0000-0002-2540-7363, Yang, William W., Davies, Julia, Varnava, Athina, Ridley, Anne J., Conlan, R. Steven and Clarkson, Richard W. E. ORCID: https://orcid.org/0000-0001-7389-8673 2020. Bcl-3 promotes multi-modal tumour cell migration via NF-kB1 mediated regulation of Cdc42. Carcinogenesis 41 (10) , pp. 1432-1443. 10.1093/carcin/bgaa005

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences European Cancer Stem Cell Research Institute (ECSCRI)
ISSN:	0147-4006
Date of First Compliant Deposit:	16 January 2020
Date of Acceptance:	15 January 2020
Last Modified:	27 Nov 2024 07:45
URI:	https://orca.cardiff.ac.uk/id/eprint/128676

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