Constitutive androgen receptor activity sustains DNA replication programs in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking effective targeted therapies. Despite AR expression in nearly half of TNBCs, androgen receptor signaling inhibitors (ARSIs) have shown minimal clinical benefit. In this study, we utilized HP518, a potent PROTAC that selectively degrades AR, to interrogate the role of AR in TNBC. We uncover a non-canonical, androgen-independent function of AR in AR-positive TNBC cells: AR cooperates with transcriptional regulators FoxA1 and GATA3 to promote expression of DNA replication genes critical for tumor proliferation. Genetic and pharmacological degradation of AR suppresses tumor cell growth, downregulates key DNA replication genes, and disrupts AR-associated transcriptional complexes. In AR-positive TNBC patient-derived xenografts (PDX), HP518 robustly inhibits tumor growth and synergizes with PI3Kα inhibition and chemotherapy. Our findings identify a previously unappreciated mechanism of AR action in TNBC and support AR degradation-not antagonism as a rational therapeutic strategy.