LAUSR

Simple Summary Despite recent therapeutic advances in the treatment of prostate cancer, metastatic castration-resistant prostate cancer continues to cause significant morbidity and mortality. New research into highly expressed proteins in metastatic castration-resistant prostate cancer shows that Six-Transmembrane Epithelial Antigen of the Prostate 1–4 (STEAP1–4) are significant drivers of prostate cancer aggressiveness and metastasis. STEAP1, in particular, is highly expressed on the plasma membrane of prostate cancer cells and has received significant attention as a potential therapeutic target. This review highlights what is known about STEAP1–4 and identifies knowledge gaps that require further research. Abstract Six-Transmembrane Epithelial Antigen of the Prostate 1–4 (STEAP1–4) compose a family of metalloproteinases involved in iron and copper homeostasis and other cellular processes. Thus far, five homologs are known: STEAP1, STEAP1B, STEAP2, STEAP3, and STEAP4. In prostate cancer, STEAP1, STEAP2, and STEAP4 are overexpressed, while STEAP3 expression is downregulated. Although the metalloreductase activities of STEAP1–4 are well documented, their other biological functions are not. Furthermore, the properties and expression levels of STEAP heterotrimers, homotrimers, heterodimers, and homodimers are not well understood. Nevertheless, studies over the last few decades have provided sufficient impetus to investigate STEAP1–4 as potential biomarkers and therapeutic targets for prostate cancer. In particular, STEAP1 is the target of many emerging immunotherapies. Herein, we give an overview of the structure, physiology, and pathophysiology of STEAP1–4 to provide context for past and current efforts to translate STEAP1–4 into the clinic.