Discovery and evaluation of novel biomarkers reveal dasatinib as a potential treatment for a specific subtype of Triple-Negative Breast Cancer

Abstract Triple-negative breast cancer (TNBC) represents the most heterogeneous and aggressive subtype of breast carcinomas, characterized by the absence of clinical biomarkers (ERα, PR, and HER2) and the lack of targeted therapies. In this regard, several clinical trials have consistently failed to effectively stratify patients and identify specific treatments that elicit substantial responses. This study aims to pinpoint biomarkers expressed exclusively in the basal mammary epithelial compartment, facilitating a refined subclassification of this breast cancer subtype. Using computational analyses of single-cell RNA sequencing data, we have identified a list of genes associated with basal identity (BC-markers). Histological validation in 137 human samples has enabled us to categorize TNBC patients into BC-positive and BC-negative TNBC subtypes. Significantly, the presence of these markers correlates with a poorer prognosis in TNBC patients. Functional analyses have revealed a pivotal role for TAGLN in cell migration, likely influencing tumor aggressiveness. Further, we discovered that BC-marker expression is associated with the mesenchymal phenotype and increased sensitivity to the tyrosine kinase inhibitor dasatinib, particularly in BC-positive TNBC, suggesting novel therapeutic avenues. In our study, TAGLN emerged as a potential predictive biomarker for dasatinib responsiveness, offering new directions for personalized therapy for TNBC patients.