Decoding the Molecular Drivers of Epithelial to Mesenchymal Transition in Breast Cancer: Insights into Epithelial Plasticity and Microenvironment Crosstalk

Recent evidence indicates that both epithelial-to-mesenchymal transition (EMT) and its reverse process, mesenchymal-to-epithelial transition (MET), are key mechanisms driving breast cancer (BC) metastasis. During EMT, epithelial BC cells acquire mesenchymal traits that enhance motility, invasiveness, and resistance to therapy. A deeper understanding of EMT regulation may therefore unveil novel therapeutic targets to limit disease progression. In this study, we analyzed the expression of key EMT-associated proteins, namely Vimentin, E-cadherin, Cytokeratin-18, and alpha-smooth muscle actin, in a cohort of 95 BC tissue samples and observed marked intra- and inter-tumoral heterogeneity. Notably, we found positive correlations between epithelial and mesenchymal markers, supporting the presence of hybrid epithelial/mesenchymal phenotypes and substantial cellular plasticity, which may contribute to BC heterogeneity. High heterogeneity in marker expression was also detected between tumor tissues and matched adjacent normal tissues. The unexpected complexity uncovered at the protein level prompted us to question whether single markers or limited proteomic panels are sufficient to capture the EMT landscape in BC. Through integrative bioinformatics, we defined a novel EMT gene signature significantly associated with prognosis. Functional enrichment revealed pathways related to extracellular matrix organization, proteoglycans, and intercellular communication, emphasizing the dynamic bidirectional crosstalk between BC cells and the tumor microenvironment. Moreover, we identified a gene cluster linked to cancer stem cell-like features, which may be clinically relevant for patient risk stratification. Overall, our findings underscore the complexity of EMT regulation in BC and introduce a new EMT signature with potential prognostic and therapeutic relevance.