Tumor microenvironment and key signaling pathways in breast cancer progression and therapy resistance: A review

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Breast cancer progression is influenced not only by intrinsic tumor alterations but also by reciprocal interactions with the tumor microenvironment (TME), a complex ecosystem comprising fibroblasts, immune and endothelial cells, adipocytes, extracellular matrix components, soluble mediators, and extracellular vesicles. This review synthesizes recent basic and translational research on how TME-derived signals activate dysregulated signaling pathways, including the phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR), transforming growth factor beta/SMAD (TGF-β/SMAD), Janus kinase/signal transducer and activator of transcription (JAK/STAT), mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), Wingless-related integration site/beta-catenin (Wnt/β-catenin), Notch, Yes-associated protein/transcriptional co-activator with PDZ-binding motif (YAP/TAZ), and nuclear factor kappa B (NF-κB). These pathways promote key processes such as invasion, angiogenesis, adaptation to hypoxia, epithelial-mesenchymal transition, immune evasion, cancer stemness, and therapy resistance. We emphasize convergent findings that indicate the feedback loop between tumor cells and the TME sustains plasticity and drug-tolerant states. Additionally, we summarize emerging therapeutic strategies, including stromal and extracellular matrix normaliza

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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