Abstract
Objective
Breast cancer (BC) is a major global health issue for women. Although insulin resistance (IR) and circadian disruption are both associated with BC, their interaction remains unclear. This study examined the association between circadian syndrome (CircS) and BC, and explored the mediating role of the triglyceride-glucose (TyG) index and related molecular mechanisms.
Methods
This cross-sectional study analyzed 5,498 women from the NHANES 2005–2014. Multivariate logistic regression assessed the association between CircS and BC, with mediation analysis to evaluate TyG’s indirect effect. Bioinformatics validation used TCGA-BRCA data, including differential expression of TyG and circadian rhythm-related gene sets, survival analysis, and pathway enrichment.
Results
Among 5,498 participants, 158 had BC. After adjusting for sociodemographic, lifestyle, and cardiovascular factors, CircS was significantly associated with higher BC risk (OR = 2.07, 95% CI: 1.12–3.83). Each one-unit increase in the TyG index was also linked to increased BC risk (OR = 1.64, 95% CI: 1.20–2.23). Mediation analysis showed the TyG index mediated 10.84% of CircS’s effect on BC (Indirect Effect: 0.0042, 95% CI: 0.0011–0.0103). Bioinformatics analysis identified dysregulated prognostic circadian rhythm DEGs and insulin receptor DEGs in tumors, and their expression correlated with overall survival. These genes were co-enriched in oncogenic pathways such as lipid metabolism and MAPK signaling.
Conclusions
This nationally representative study indicates that CircS is strongly associated with a higher prevalence of BC, with IR—measured by the TyG index—partially mediating this association. Molecular evidence shows that circadian and metabolic disruptions converge on key signaling pathways, suggesting a synergistic role in BC development.