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Masaki Shiota Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Shusuke Akamatsu Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

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Shigehiro Tsukahara Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Shohei Nagakawa Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Takashi Matsumoto Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Masatoshi Eto Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Hormonal therapies including androgen deprivation therapy and androgen receptor (AR) pathway inhibitors such as abiraterone and enzalutamide have been widely used to treat advanced prostate cancer. However, treatment resistance emerges after hormonal manipulation in most prostate cancers, and it is attributable to a number of mechanisms, including AR amplification and overexpression, AR mutations, the expression of constitutively active AR variants, intra-tumor androgen synthesis, and promiscuous AR activation by other factors. Although various AR mutations have been reported in prostate cancer, specific AR mutations (L702H, W742L/C, H875Y, F877L, and T878A/S) were frequently identified after treatment resistance emerged. Intriguingly, these hot spot mutations were also revealed to change the binding affinity of ligands including steroids and antiandrogens and potentially result in altered responses to AR pathway inhibitors. Currently, precision medicine utilizing genetic and genomic data to choose suitable treatment for the patient is becoming to play an increasingly important role in clinical practice for prostate cancer management. Since clinical data between AR mutations and the efficacy of AR pathway inhibitors are accumulating, monitoring the AR mutation status is a promising approach for providing precision medicine in prostate cancer, which would be implemented through the development of clinically available testing modalities for AR mutations using liquid biopsy. However, there are few reviews on clinical significance of AR hot spot mutations in prostate cancer. Then, this review summarized the clinical landscape of AR mutations and discussed their potential implication for clinical utilization.

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Masaki Shiota Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Satoshi Endo United Graduate School of Medical Information Sciences, Gifu University, Gifu, Japan
Center for One Medicine Innovative Translational Research (COMIT), Gifu University, Gifu, Japan

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Shigehiro Tsukahara Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Tokiyoshi Tanegashima Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Satoshi Kobayashi Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Takashi Matsumoto Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Masatoshi Eto Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Androgen receptor signaling is crucial for the development of treatment resistance in prostate cancer. Among steroidogenic enzymes, 3β-hydroxysteroid dehydrogenases (3βHSDs) play critical roles in extragonadal androgen synthesis, especially 3βHSD1. Increased expression of 3βHSDs is observed in castration-resistant prostate cancer tumors compared with primary prostate tumors, indicating their involvement in castration resistance. Recent studies link 3βHSD1 to resistance to androgen receptor signaling inhibitors. The regulation of 3βHSD1 expression involves various factors, including transcription factors, microenvironmental influences, and posttranscriptional modifications. Additionally, the clinical significance of HSD3B1 genotypes, particularly the rs1047303 variant, has been extensively studied. The impact of HSD3B1 genotypes on treatment outcomes varies according to the therapy administered, suggesting the potential of HSD3B1 genotyping for personalized medicine. Targeting 3βHSDs may be a promising strategy for prostate cancer management. Overall, understanding the roles of 3βHSDs and their genetic variations may enable the development and optimization of novel treatments for prostate cancer.

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