Suppression of Bcl3 disrupts viability of breast cancer cells through both p53-dependent and p53-independent mechanisms via loss of NF-κB signalling

Turnham, Daniel J.; Smith, Hannah; Clarkson, Richard W. E.

Abstract

The NF-κB co-factor Bcl3 is a proto-oncogene that promotes breast cancer proliferation, metastasis and therapeutic resistance, yet its role in breast cancer cell survival is unclear. Here, we sought to determine the effect of Bcl3 suppression alone on breast cancer cell viability, with a view to informing future studies that aim to target Bcl3 therapeutically. Bcl3 was suppressed by siRNA in breast cancer cell lines before changes in viability, proliferation, apoptosis and senescence were examined. Bcl3 suppression significantly reduced viability and was shown to induce apoptosis in all cell lines tested, while an additional p53-dependent senescence and senescence-associated secretory phenotype was also observed in those cells with functional p53. The role of the Bcl3/NF-κB axis in this senescence response was confirmed via siRNA of the non-canonical NF-κB subunit NFKB2/p52, which resulted in increased cellular senescence and the canonical subunit NFKB1/p50, which induced the senescence-associated secretory phenotype. An analysis of clinical data showed a correlation between reduced relapse-free survival in patients that expressed high levels of Bcl3 and carried a p53 mutation. Together, these data demonstrate a dual role for Bcl3/NF-κB in the maintenance of breast cancer cell viability and suggests that targeting Bcl3 may be more beneficial to patients with tumours that lack functional p53.

• Journal Article Type: Article
• Acceptance Date: Jan 5, 2024
• Online Publication Date: Jan 10, 2024
• Publication Date: Jan 24, 2024
• Deposit Date: Oct 22, 2024
• Publicly Available Date: Oct 23, 2024
• Journal: Biomedicines
• Electronic ISSN: 2227-9059
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 12
• Issue: 1
• Article Number: 143
• DOI: https://doi.org/10.3390/biomedicines12010143
• Public URL: https://uwe-repository.worktribe.com/output/13307312