A Molecular Switch from Tumor Suppressor to Oncogene in ER-Positive Breast Cancer: Role of Androgen Receptor, JAK-STAT, and Lineage Plasticity [AR low/high]

Cancers develop resistance to inhibitors of oncogenes mainly due to target-centric mechanisms such as mutations and splicing. While inhibitors or antagonists force targets to unnatural conformation contributing to protein instability and resistance, activating tumor suppressors may maintain the protein in an agonistic conformation to elicit sustainable tumor growth inhibition. Due to lack of tumor suppressor-agonists, this hypothesis and mechanisms underlying resistance are not understood. In estrogen receptor (ER)-positive breast cancer (BC), androgen receptor (AR) is a druggable tumor suppressor and offers a promising avenue for this investigation. Spatial genomics suggest that the molecular portrait of AR-expressing BC cells in tumor microenvironment corresponds to better overall patient survival, clinically confirming AR’s role as a tumor suppressor. Ligand-activation of AR-positive BC xenografts reprograms cistromes, inhibits oncogenic pathways, and promotes cellular elasticity towards a more differentiated state, while sustained treatment results in cistromes rearrangement towards transcription factor PROP1, transformation of AR into an oncogene, and activation of the JAK/STAT pathway, all culminating in lineage plasticity to an aggressive resistant subtype. While the molecular profile of AR agonist-sensitive tumors corresponds to better patient survival, the profile represented in the resistant phenotype corresponds to shorter survival. Inhibition of activated oncogenes in resistant tumors reduces growth and re-sensitizes them to AR agonists. Together, these findings indicate that persistent activation of a tumor suppressor is not fail-safe and leads to resistance through lineage plasticity-driven tumor metamorphosis. Our work provides a framework to explore the above phenomenon across multiple cancer types and underscores the importance of factoring the sensitization of tumor suppressor targets while developing agonist-like drugs