An Update on the Role of Androgens and Androgen Receptor in Triple-Negative Breast Cancer

Abstract

Androgen receptor (AR) signaling has emerged as a potential molecular target in triple-negative breast cancer (TNBC), a clinically aggressive and biologically heterogeneous subtype of breast cancer with limited targeted treatment options. Androgens, the main ligands of AR, have been reported to exert antiproliferative and anti-estrogenic effects in normal mammary epithelium; however, the role of AR signaling in TNBC remains controversial and appears to depend strongly on tumor molecular context. In certain experimental settings, elevated androgen levels have been associated with reduced tumor growth, whereas AR activation has also been linked to signaling pathways involved in cell survival, migration, and invasiveness. AR signaling can occur through classical androgen-dependent mechanisms, as well as through ligand-independent activation mediated by protein kinases and intracellular pathways. Increasing interest in AR biology has led to the evaluation of several anti-androgen therapies in AR-positive TNBC, including agents such as enzalutamide, enobosarm, orteronel, bicalutamide, and seviteronel. Although clinical activity has generally been modest, these studies highlight the potential relevance of AR-targeted strategies in selected patient subgroups. This review summarizes current knowledge on androgen and AR signaling in TNBC, integrating molecular mechanisms, preclinical evidence, and clinical studies, and discusses emerging therapeutic strategies aimed at improving patient treatment outcomes