Differential impact of classical and non-canonical NF-κB pathway-related gene expression on the survival of breast cancer patients

Background:

Inflammation is a well-known driver of carcinogenesis and cancer progression, often attributed to the tumor microenvironment. The NF-κB signaling pathway is an important connection between inflammation and tumorigenesis. However, the role of the NF-κB pathway in the survival of breast cancer patients is only poorly studied. In this study, we analyzed and related the expression of both canonical and alternative NF-κB pathways and selected target genes with the relapse-free and overall survival of breast cancer patients.

Methods:

We used the transcriptomics-based public dataset of the Kaplan-Meier plotter (kmplot) to determine overall survival (OS) and relapse-free survival (RFS) of 3951 breast cancer patients. Gene expression was also determined by qPCR in a set of 7 breast cancer cell lines representative of different molecular subtypes.

Results:

The expression of IKKα was associated with poor relapse-free survival in patients with ER-positive tumors. Moreover, the expression of IL-8 and MMP-1 was associated with poor relapse-free and overall survival. In contrast, expression of IKKβ, p50, and p65 from the canonical pathway, and NIK and RELB from the alternative pathway correlated with better relapse-free survival also when the patients were classified by their hormonal and nodal status. Expression data in cell lines revealed association of some NF-κB pathway compounds with a more aggressive phenotype.

Conclusions:

Our study suggests that activation of the canonical and alternative NF-κB pathways is ultimately critical for tumor survival. Understanding the communication between both pathways would help to find better therapeutic and prophylactic targets to prevent breast cancer progression and relapse.