Steroid receptor coactivators: from basic research to translational opportunities

The concept of nuclear receptor (NR) coregulation was proposed nearly 2 decades before it was experimentally validated. According to this model, NRs-executors of a vast array of transcriptional programs-do not act independently but are governed by a network of regulatory proteins that either activate or repress their biological function. Nuclear receptors identify the genes to be regulated. However, coregulators ultimately serve as the true controllers of transcriptional outcomes. They recruit cofactors and coordinate the activity of transcriptional complexes, thereby shaping NR-mediated gene expression beyond NRs' intrinsic functionality. The steroid receptor coactivator (SRC) family is the most extensively studied and functionally dominant group of NR coregulators, modulating nearly all gene activities. The pleiotropic biological roles of SRCs-spanning key physiological and pathological processes-make them compelling therapeutic targets. Here, we outline the evolution of the coregulation concept, which reached a critical milestone with the discovery of the SRC family. We highlight the central roles of SRCs in both physiology and oncology and trace the development of therapeutic strategies aimed at targeting these proteins.