A novel prognostic signature based on epithelial-mesenchymal transition-associated genes for the prognosis and immune status in breast cancer.

[OBJECTIVE] Breast cancer (BC) incidence continues to rise, and recurrence and metastasis remain major contributors to mortality. The epithelial-mesenchymal transition (EMT), associated with the acquisition of invasive functions by epithelial cells, also promotes resistance to anticancer therapies. Here, an EMT-based prognostic model was developed to enhance BC outcome prediction.

[METHODS] Clinical and gene expression data from the TCGA were randomly assigned to discovery and validation cohorts. Univariate Cox regression and LASSO analyses were utilized to develop a prognostic signature. The Cell-Type Identification by Estimating Relative Subsets of RNA Transcripts and ESTIMATE algorithms were applied to evaluate the tumor microenvironment (TME). Enriched immune-associated pathways were found using GSEA. SDC1 was knocked down and overexpressed in MCF-7 and MDA-MB-231 cells, and its effects on cell proliferation, apoptosis, migration, invasion and EMT key markers were evaluated by CCK-8, flow cytometry, Transwell and Western blot.

[RESULTS] Ten EMT-related genes (TP63, TFPI2, ALX4, F2RL2, LEF1, PDLIM4, NDRG2, HMGB3, SDC1, and KRT17) showed significant links with overall survival. The resulting signature was used to allocate individuals into high- and low-risk groups with distinct prognoses in both cohorts. M0 macrophages, activated natural killer cells, memory-activated CD4 T cells, and immunological scores were all lower in high-risk patients. GSEA revealed that the low-risk group demonstrated greater enrichment in immune-related pathways, including cell adhesion molecules, cytokine-cytokine receptor interactions, and T-cell receptor signaling. SDC1 expression was markedly raised in tumor tissues and correlated with several clinical and pathological features. Knockdown of SDC1 in vitro inhibited the proliferation, migration and invasion of BC cells, induced apoptosis and reversed EMT process. Overexpression of SDC1 had the opposite cancer-promoting effect.

[CONCLUSION] This ten-gene EMT-based signature reliably predicts BC prognosis and offers valuable insight into the tumor immune microenvironment.