Interleukin-3-Receptor-α in Triple-Negative Breast Cancer (TNBC): An Additional Novel Biomarker of TNBC Aggressiveness and a Therapeutic Target

SIMPLE SUMMARY: Molecular and histological profiling is crucial for biomarker and therapeutic target discovery, for example, in TNBC. We demonstrated that IL-3Rα expression led to the identification of a subgroup of TNBC patients displaying a poor overall survival. Moreover, we refined TNBC molecular annotation and drew a model including IL-3Rα, PD-L1, and genes related to EMT, which finely discriminates cancer aggressiveness. Finally, we first demonstrated that IL-3Rα is instrumental in granting tumour adaptation and progression by reprogramming TNBC cells to form large dysfunctional vessels and reshaping PD-L1 expression in primary tumours and metastases. Therefore, the IL-3/IL-3Rα axis may be proposed as a marker of TNBC aggressiveness, as a novel TNBC therapeutic challenge. ABSTRACT: Tumour molecular annotation is mandatory for biomarker discovery and personalised approaches, particularly in triple-negative breast cancer (TNBC) lacking effective treatment options. In this study, the interleukin-3 receptor α (IL-3Rα) was investigated as a prognostic biomarker and therapeutic target in TNBC. IL-3Rα expression and patients’ clinical and pathological features were retrospectively analysed in 421 TNBC patients. IL-3Rα was expressed in 69% human TNBC samples, and its expression was associated with nodal metastases (p = 0.026) and poor overall survival (hazard ratio = 1.50; 95% CI = 1.01–2.2; p = 0.04). The bioinformatics analysis on the Breast Invasive Carcinoma dataset of The Cancer Genome Atlas (TCGA) proved that IL-3Rα was highly expressed in TNBC compared with luminal breast cancers (p = 0.017, padj = 0.026). Functional studies demonstrated that IL-3Rα activation induced epithelial-to-endothelial and epithelial-to-mesenchymal transition, promoted large blood lacunae and lung metastasis formation, and increased programmed-cell death ligand-1 (PD-L1) in primary tumours and metastases. Based on the TCGA data, IL-3Rα, PD-L1, and EMT coding genes were proposed to discriminate against TNBC aggressiveness (AUC = 0.86 95% CI = 0.82–0.89). Overall, this study identified IL-3Rα as an additional novel biomarker of TNBC aggressiveness and provided the rationale to further investigate its relevance as a therapeutic target.