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

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 normalization, immunotherapy combinations, pathway-targeted inhibitors, and nanotechnology-enabled drug delivery. A comprehensive understanding of TME-signaling crosstalk is crucial for overcoming therapeutic resistance in breast cancer.