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

Figure 3 Unhealthy diets and obesity converge to drive breast carcinogenesis through two interconnected axes. Created in BioRender. Systemic metabolic dysfunction - characterized by hyperinsulinaemia, elevated pro-inflammatory cytokines (interleukin-6, tumor necrosis factor), and accumulation of advanced glycation end products - and gut microbiota dysbiosis, which reduces beneficial short-chain fatty acids while increasing harmful metabolites such as lipopolysaccharides and leucine. These systemic and microbial effectors collectively activate key oncogenic pathways including phosphatidylinositol 3-kinase/protein kinase B/mammalian/mechanistic target of rapamycin, Janus kinase/signal transducer and activator of transcription, and Wnt/β-catenin, and remodel the tumour immune microenvironment via leucine-mediated expansion of polymorphonuclear myeloid-derived suppressor cells and lipopolysaccharides-triggered chronic inflammation, ultimately fostering tumour proliferation, invasion, metastasis, and therapy resistance. IL-6: Interleukin-6; TNF: Tumor necrosis factor; PI3K: Phosphatidylinositol 3-kinase; Akt: Protein kinase B; mTOR: Mammalian/mechanistic target of rapamycin; JAK: Janus kinase; STAT: Signal transducer and activator of transcription; LPS: Lipopolysaccharide; SCFAs: Short-chain fatty acids; AGEs: Advanced glycation end products; PMN-MDSCs: Polymorphonuclear myeloid-derived suppressor cells.