BCL-3 loss sensitises colorectal cancer cells to DNA damage by targeting homologous recombination

Parker, Christopher, Chambers, Adam C., Flanagan, Dustin J., Ho, Jasmine Wing Yu, Collard, Tracey J., Ngo, Greg, Baird, Duncan M. ORCID: https://orcid.org/0000-0001-8408-5467, Timms, Penny, Morgan, Rhys G., Sansom, Owen J. and Williams, Ann C. 2022. BCL-3 loss sensitises colorectal cancer cells to DNA damage by targeting homologous recombination. DNA Repair 115 , 103331. 10.1016/j.dnarep.2022.103331

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Abstract

The proto-oncogene BCL-3 is upregulated in a subset of colorectal cancers (CRC), where it has been shown to enhance tumour cell survival. However, although increased expression correlates with poor patient prognosis, the role of BCL-3 in determining therapeutic response remains largely unknown. In this study, we use combined approaches in multiple cell lines and pre-clinical mouse models to investigate the function of BCL-3 in the DNA damage response. We show that suppression of BCL-3 increases γH2AX foci formation and decreases homologous recombination in CRC cells, resulting in reduced RAD51 foci number and increased sensitivity to PARP inhibition. Importantly, a similar phenotype is seen in Bcl3-/- mice, where Bcl3-/- mouse crypts also exhibit sensitivity to DNA damage with increased γH2AX foci compared to wild type mice. Additionally, Apc.Kras-mutant x Bcl3-/- mice are more sensitive to cisplatin chemotherapy compared to wild type mice. Taken together, our results identify BCL-3 as a regulator of the cellular response to DNA damage and suggests that elevated BCL-3 expression, as observed in CRC, could increase resistance of tumour cells to DNA damaging agents including radiotherapy. These findings offer a rationale for targeting BCL-3 in CRC as an adjunct to conventional therapies and suggest that BCL-3 expression in tumours could be a useful biomarker in stratification of rectal cancer patients for neo-adjuvant chemoradiotherapy.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Publisher:	Elsevier
ISSN:	1568-7864
Date of First Compliant Deposit:	28 April 2022
Date of Acceptance:	13 April 2022
Last Modified:	16 May 2023 12:43
URI:	https://orca.cardiff.ac.uk/id/eprint/149425

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