We coalesce these mechanistic insights to propose that AR has two distinct modes of interacting with chromatin: 1) NSD2-independent binding at cis-elements harboring canonical full AREs that are predominantly found in the physiological enhancer circuitry, and 2) NSD2-dependent binding at cis-regulatory elements harboring chimeric AR half-motifs (like FOXA1:AR half) that distinctively constitute the cancer-specific enhancer circuitries of AR (Fig. 5). The gene discussed is NSD2; the disease is cancer.