The Androgen Receptor is a Tumor Suppressor in Estrogen Receptor Positive Breast Cancer [ZR-75-1 cell line RNA-seq]

The role of the androgen receptor (AR) in estrogen receptor alpha (ER) positive breast cancer is controversial, constraining implementation of AR-directed therapies. Using a diverse, clinically relevant panel of cell-line and patient-derived models, we demonstrate that AR activation, not suppression, exerts potent anti-tumor activity in multiple disease contexts, including resistance to standard-of-care ER and CDK4/6 inhibitors. Importantly, AR agonists combined with standard-of-care agents enhanced therapeutic responses. Mechanistically, agonist activation of AR altered the genomic distribution of ER and essential co-activators (p300, SRC-3), resulting in repression of ER-regulated cell cycle genes and up-regulation of AR target genes, including known tumor suppressors. A gene signature of AR activity positively predicted disease survival in multiple clinical ER+ breast cancer cohorts. These findings provide unambiguous evidence that AR has a tumor suppressor role in ER+ breast cancer and support AR agonism as the optimal AR-directed treatment strategy, revealing a rational therapeutic opportunity. Overall design: RNA-seq of ZR-75-1 cells cultured in steroid-depleted conditions then treated for 4 hours with E2 or E2+DHT (10 nM each).