Unraveling the role of IL-17 signaling pathway in breast cancer-related depression: insights from in vivo/in vitro models and transcriptomic analysis.

Abstract

Breast cancer-related depression (BCRD) is a prevalent comorbidity that markedly reduces quality of life and can negatively influence treatment outcomes. The molecular basis of BCRD remains elusive, particularly the role of the IL-17 signaling pathway in the interaction between breast cancer and depression. We established a BCRD mouse model by inducing breast tumors and administering chronic corticosterone. Transcriptomic analysis was performed on brain and tumor tissues to identify differentially expressed genes (DEGs) associated with BCRD. Functional enrichment analyses were conducted to determine the biological functions and signaling pathways linked to these DEGs. For in vitro validation, lipopolysaccharide (LPS)-stimulated BV2 microglia cells were used to mimic neuroinflammation, and the effects of modulating IL-17 signaling on cellular activation were assessed. In vivo, BCRD mice exhibited increased immobility time in the tail suspension test and reduced sucrose preference, indicative of depressive-like behaviors. Transcriptomic analysis revealed substantial changes in immune-related genes, particularly those involved in the IL-17 signaling pathway. In vitro, LPS stimulation elevated IL-17, NF-κB p65, and other inflammatory markers in BV2 cells, whereas IL-17 inhibition attenuated these responses. Furthermore, we observed increased expression of IL-17 and NF-κB p65 in the brain tissues of BCRD mice, which was associated with increased microglial activation and blood-brain barrier permeability. These findings demonstrate that the IL-17 signaling pathway plays a crucial role in BCRD development, linking breast cancer progression to depressive symptoms through microglia activation and disruption of the blood-brain barrier. Targeting the IL-17 signaling pathway may offer a promising therapeutic strategy for treating BCRD.