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

## TL;DR

This study explores how breast cancer cells change their properties and interact with their environment, identifying a new gene signature that could help predict outcomes and guide treatment.

## Contribution

A novel EMT gene signature is identified, offering potential for improved prognosis and therapeutic strategies in breast cancer.

## Key findings

- Breast cancer tissues show high heterogeneity in EMT marker expression, including hybrid epithelial/mesenchymal phenotypes.
- A new EMT gene signature is significantly associated with prognosis and highlights tumor-microenvironment interactions.
- A gene cluster linked to cancer stem cell-like features is identified, which may aid in patient risk stratification.

## Abstract

Epithelial-to-mesenchymal transition (EMT) is a hallmark of cancer and plays a critical role in breast cancer progression. Here, we analyzed the expression of EMT-related markers, including Vimentin, E-cadherin, Cytokeratin-18, and α-SMA, in a cohort of 95 breast cancer tissue samples, revealing marked intra- and inter-tumoral heterogeneity. Positive correlations between epithelial and mesenchymal markers supported the presence of hybrid epithelial/mesenchymal phenotypes and high cellular plasticity. The investigation of the molecular basis of this plasticity was performed by integrative bioinformatics analyses, leading to the identification of a novel EMT gene signature significantly associated with prognosis. Functional enrichment analyses underscored the dynamic interplay between tumor cells and microenvironment. Moreover, a gene cluster associated with cancer stem cell-like features that may be clinically relevant for patient risk stratification was identified. Overall, our findings emphasize the complexity of EMT regulation in breast cancer and propose a new EMT signature with potential prognostic/therapeutic relevance.

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.