Association between insulin resistance and breast cancer risk in perimenopausal and postmenopausal women: mediating effects of oxidative stress and inflammatory biomarkers

Background: Insulin resistance is implicated in breast carcinogenesis, but the comparative performance of different surrogate indices in associating with breast cancer risk among perimenopausal and postmenopausal women remains unclear. Methods: We analyzed data from 7,713 peri-/postmenopausal women from the National Health and Nutrition Examination Survey (1999–2020). Four insulin resistance indices, namely, the triglyceride-glucose index (TyG), triglyceride-to-high-density lipoprotein cholesterol ratio (TG/HDL-C), homeostasis model assessment of insulin resistance (HOMA-IR), and metabolic score for insulin resistance (METS-IR), were assessed. Boruta algorithm-based feature selection preceded weighted multivariate logistic regression, estimating associations with prevalent self‑reported breast cancer. Restricted cubic spline method was used to test for nonlinearity. Mediation analysis explored mechanisms, whereas Cox regression was used to evaluate mortality. Results: The TyG index was associated with higher odds of prevalent breast cancer, both as a continuous variable (OR = 1.52; 95% CI: 1.14–2.04; P = 0.005) and in its highest quartile (OR = 2.45; 95% CI: 1.18–5.07; P = 0.017, P for trend = 0.009),with a roughly linear pattern. HOMA-IR showed a weaker, nonlinear association concentrated only in the highest quartile (OR = 2.46, 95% CI: 1.29–4.69; P = 0.007; P for trend = 0.013). TG/HDL-C and METS-IR were not consistently related. Uric acid to high-density lipoprotein cholesterol (UHR, 33.84%) and the neutrophil-to-platelet ratio (NPR, 7.11%) partially mediated the effect of TyG ( P < 0.05). Cox regression showed that the TyG index increased all-cause (HR = 1.67; 95% CI: 1.49–1.86; P < 0.001) and cancer mortality (HR = 1.57; 95% CI: 1.27–1.93; P < 0.001), but not among the subgroup of women with prevalent breast cancer. Conclusions: In a nationally representative sample of peri-/postmenopausal women, TyG was associated with higher odds of prevalent breast cancer. Oxidative stress (UHR) and inflammation (NPR) may partially explain this relationship. Graphical abstract