Figure 2.

AR signaling pathway and targeted therapeutic strategies against AR. AR can regulate the proliferation, migration, and invasiveness in BC through genomic and/or nongenomic pathways. CYP17A1 is the enzyme that converts androgen precursors into DHEA, HSD3β1 catalyzes DHEA to AD, while AKR1C3 converts AD to testosterone; finally, testosterone is catalyzed to DHT by 5α-reductase. In the genomic way of AR activation, DHT binds and activates AR, which disassociates from heat shock proteins and forms dimers, which translocate to the nucleus, where gene transcription is modulated by binding to the androgen response elements of target genes. In the nongenomic way of AR activation, ERK-mediated AR signaling involves phosphoinositide 3-kinase (PI3K), Src proteins, and Ras GTPase. Abiraterone acetate selectively and irreversibly blocks CYP17A1 activity. Drugs: Seviteronel is a CYP17A1 inhibitor. Bicalutamide is a first-generation and Enzalutamide a second-generation AR antagonist that blocks androgens binding to AR. Enzalutamide also inhibits AR nuclear translocation and AR-mediated transcription. In the nongenomic way of AR activation, the use of AR antagonists/inhibitors of AR-activated proteins that disrupts the AR/src association could be a starting point to reduce BC cell proliferation. Abbreviations: AD—androstenedione; AKR1C3—aldo-keto reductase family 1 member C3; AP—androgen precursors; AR—androgen receptor; ARE—androgen receptor element; CYP17A1—cytochrome P450 c17; DHEA—dehydroepiandrosterone; DHT—dihydrotestosterone; HSP—heat shock protein; HSD3β1—human 3-beta-hydroxysteroid dehydroxynase/delta5-4 isomerase type 1; T—testosterone; TF—transcription factor.