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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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Mitsuyo Matsumoto Departments of, Medical Technology, Obstetrics and Gynecology, Pathology, Research Institute for Clinical Oncology, Division of Breast Surgery, Tohoku University School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai 981-0872, Japan
Departments of, Medical Technology, Obstetrics and Gynecology, Pathology, Research Institute for Clinical Oncology, Division of Breast Surgery, Tohoku University School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai 981-0872, Japan

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Yuri Yamaguchi Departments of, Medical Technology, Obstetrics and Gynecology, Pathology, Research Institute for Clinical Oncology, Division of Breast Surgery, Tohoku University School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai 981-0872, Japan

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Yuko Seino Departments of, Medical Technology, Obstetrics and Gynecology, Pathology, Research Institute for Clinical Oncology, Division of Breast Surgery, Tohoku University School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai 981-0872, Japan

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Atsushi Hatakeyama Departments of, Medical Technology, Obstetrics and Gynecology, Pathology, Research Institute for Clinical Oncology, Division of Breast Surgery, Tohoku University School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai 981-0872, Japan

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Hiroyuki Takei Departments of, Medical Technology, Obstetrics and Gynecology, Pathology, Research Institute for Clinical Oncology, Division of Breast Surgery, Tohoku University School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai 981-0872, Japan

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Hitoshi Niikura Departments of, Medical Technology, Obstetrics and Gynecology, Pathology, Research Institute for Clinical Oncology, Division of Breast Surgery, Tohoku University School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai 981-0872, Japan

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Kiyoshi Ito Departments of, Medical Technology, Obstetrics and Gynecology, Pathology, Research Institute for Clinical Oncology, Division of Breast Surgery, Tohoku University School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai 981-0872, Japan

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Takashi Suzuki Departments of, Medical Technology, Obstetrics and Gynecology, Pathology, Research Institute for Clinical Oncology, Division of Breast Surgery, Tohoku University School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai 981-0872, Japan

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Hironobu Sasano Departments of, Medical Technology, Obstetrics and Gynecology, Pathology, Research Institute for Clinical Oncology, Division of Breast Surgery, Tohoku University School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai 981-0872, Japan

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Nobuo Yaegashi Departments of, Medical Technology, Obstetrics and Gynecology, Pathology, Research Institute for Clinical Oncology, Division of Breast Surgery, Tohoku University School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai 981-0872, Japan

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Shin-ichi Hayashi Departments of, Medical Technology, Obstetrics and Gynecology, Pathology, Research Institute for Clinical Oncology, Division of Breast Surgery, Tohoku University School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai 981-0872, Japan

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The estrogen pathway plays an important role in the etiology of human endometrial carcinoma (EC). We examined whether estrogen biosynthesis in the tumor microenvironment promotes endometrial cancer. To examine the contribution of stromal cells to estrogen signaling in EC, we used reporter cells stably transfected with the estrogen response element (ERE) fused to the destabilized green fluorescent protein (GFP) gene. In this system, the endometrial cancer stromal cells from several patients activated the ERE of cancer cells to a variable extent. The GFP expression level increased when testosterone, a substrate for aromatase, was added. The effect was variably inhibited by aromatase inhibitors (AIs), although the response to AIs varied among patients. These results suggest that GFP expression is driven by estrogen synthesized by aromatase in the endometrial cancer stromal cells. In a second experiment, we constructed an adenovirus reporter vector containing the same construct as the reporter cells described above, and visualized endogenous ERE activity in primary culture cancer cells from 15 EC specimens. The GFP expression levels varied among the cases, and in most primary tissues, ERE activities were strongly inhibited by a pure anti-estrogen, fulvestrant. Interestingly, a minority of primary tissues in endometrial cancer showed ERE activity independent of the estrogen-ER pathway. These results suggest that AI may have some therapeutic value in EC; however, the hormonal microenvironment must be assessed prior to initiating therapy.

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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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