FKBP52 in cancer biology and therapy: molecular mechanisms, signalling networks, and drug targeting of the FKBP protein family

From the initial discovery of FK506 binding protein 12 (FKBP12), the FKBP familial group of proteins have since been identified to be highly conserved proteins within eukaryotes. As functional proteins, the isoforms of FKBPs display a myriad of functions within the systemic environment. FKBP proteins are known to possess roles in apoptosis, cancer, cardiac support, cell development, neuronal function, protein folding and trafficking, cell receptor signalling and transcriptional control, whilst conserved across multiple types of tissues and subcellular components. Of the 16 member FKBP family, FKBP51 and FKBP52 are the only members that exhibit a diverse role in the regulation of steroid hormone receptors. Beyond their involvement in receptor signalling, binding and nuclear translocation, studies have implicated FKBP51 and FKBP52 in the pathogenesis of a variety of hormone dependent diseases and cancers. Furthermore, selective inhibition of FKBP51 has advanced considerably, whereas FKBP52 selectivity remains an ongoing challenge. This review summarises the current mechanistic understanding of the FKBP protein family, with a focus on the roles of FKBP51 and FKBP52 in steroid hormone–driven cancers, highlighting key knowledge gaps, translational biomarkers, pre-clinical efforts and clinical progress.