Abstract
BACKGROUND: Tumor heterogeneity is widely recognized as a crucial factor impacting the prognosis of breast cancer (BC) patients. However, there remains an insufficient understanding of the underlying impact of anoikis on the prognosis of BC patients. METHODS: The researchers utilized the TCGA-BRCA dataset to screen and analyze the differentially expressed genes of anoikis-related genes (ARGs) in BC and normal breast tissue. Prognostic gene signatures were established through univariate, LASSO, and multivariate Cox regression analyses. These signatures were evaluated using Kaplan-Meier curve and receiver operating characteristic (ROC) analyses, resulting in the development of an anoikis-related index (ACI). The training dataset was TCGA-BRCA, while METABRIC and GSE96058 were used for external validation. Additionally, nomograms were developed by combining risk scores and clinical parameters, enabling gene set enrichment analysis (GSEA) and tumor immunoassay. Furthermore, an exploration of small molecule compounds was conducted to identify potential therapeutic benefits. RESULTS: A six-gene anoikis-related signature was constructed, which divided BC patients into high- and low-ACI groups based on median ACI scores. The ACI accurately predicted prognosis and acted as an independent prognostic factor for BC patients. Patients in the high-ACI group exhibited poorer overall survival (OS) across all cohorts and showed more severe clinical manifestations compared to the low-ACI group. The study also explored the potential impacts of anoikis on immune cells infiltrating tumors, immune checkpoints, growth factors, and cytokine levels. Additionally, the potential implications of anoikis in BC immunotherapy were discussed, along with highlighting small molecule compounds that could offer therapeutic benefits. CONCLUSIONS: Anoikis was found to hold significant prognostic value in breast cancer, providing a novel approach for managing patients with different prognoses and implementing more precise immunotherapy strategies.