Breast cancer and metabolic comorbidities: From epidemiology and molecular mechanisms to precision interventions

Figure 2 Systemic metabolic disturbances - including hyperinsulinemia, obesity-related inflammatory cytokines (interleukin-6, tumor necrosis factor), and metabolic metabolites - converge to activate key oncogenic pathways. Created in BioRender. Insulin resistance hyperactivates the phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycinaxis, promoting tumour growth, while insulin-like growth factor binding protein 6 acts as an endogenous inhibitor. In parallel, interleukin-6 and tumor necrosis factor activate Janus kinase/signal transducer and activator of transcription and mitogen-activated protein kinase cascades, fostering a pro-metastatic microenvironment. Wnt/β-catenin signalling is augmented by metabolic factors and constrained by secreted frizzled-related protein 4; its activity is further suppressed by soy isoflavones via peroxisome proliferator-activated receptor gamma activation and nuclear factor kappa B degradation. Together, these mechanisms illustrate how metabolic imbalance fuels breast cancer progression. IL-6: Interleukin-6; TNF: Tumor necrosis factor; PI3K: Phosphatidylinositol 3-kinase; Akt: Protein kinase B; mTOR: Mechanistic target of rapamycin; JAK: Janus kinase; STAT: Signal transducer and activator of transcription; MAPK: Mitogen-activated protein kinase; sFRP4: Secreted frizzled-related protein 4; NF-κB: Nuclear factor kappa B; PPAR-γ: Peroxisome proliferator-activated receptor gamma.