Discovery and Evaluation of Biomarkers for Triple-Negative Breast Cancer Subtypes Uncovers Patient Stratification and Targeted Therapeutic Strategies

Abstract

Triple-negative breast cancer (TNBC) is the most heterogeneous and aggressive subtype of breast carcinoma, characterized by the absence of clinical biomarkers and the lack of targeted therapies. Despite numerous clinical trials, patient stratification remains suboptimal, limiting the identification of effective treatment strategies. In this study, we aimed to identify biomarkers exclusively expressed in the basal mammary epithelial compartment to refine TNBC subclassification. Computational analysis of single-cell RNA-sequencing data defined a set of basal identity genes, which were subsequently validated by immunohistochemistry in two independent TNBC cohorts. This approach enabled the identification of a TNBC subgroup, termed true basal TNBC (tB-TNBC), which was associated with poorer prognosis. High-throughput screening of 3,200 FDA-approved compounds in breast cancer cell lines classified according to basal marker expression identified dasatinib as a promising candidate with selective activity against tB-TNBC models. In tB-TNBC patient-derived xenograft models, dasatinib treatment effectively suppressed tumor growth. Furthermore, TAGLN emerged as a strong predictive biomarker of dasatinib response, with functional studies confirming its role in modulating drug sensitivity. Altogether, these findings support the clinical utility of basal markers for TNBC stratification and highlight a targeted treatment opportunity for tB-TNBC patients.