1.Lineage plasticity-mediated therapy resistance in prostate cancer.
Alexandra M BLEE ; Haojie HUANG
Asian Journal of Andrology 2019;21(3):241-248
Therapy resistance is a significant challenge for prostate cancer treatment in clinic. Although targeted therapies such as androgen deprivation and androgen receptor (AR) inhibition are effective initially, tumor cells eventually evade these strategies through multiple mechanisms. Lineage reprogramming in response to hormone therapy represents a key mechanism that is increasingly observed. The studies in this area have revealed specific combinations of alterations present in adenocarcinomas that provide cells with the ability to transdifferentiate and perpetuate AR-independent tumor growth after androgen-based therapies. Interestingly, several master regulators have been identified that drive plasticity, some of which also play key roles during development and differentiation of the cell lineages in the normal prostate. Thus, further study of each AR-independent tumor type and understanding underlying mechanisms are warranted to develop combinational therapies that combat lineage plasticity in prostate cancer.
Androgen Antagonists/therapeutic use*
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Androgen Receptor Antagonists/therapeutic use*
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Gene Expression Regulation, Neoplastic
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Humans
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Male
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Prostatic Neoplasms/genetics*
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Prostatic Neoplasms, Castration-Resistant/genetics*
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Receptors, Androgen/drug effects*
2.The androgen receptor in hormone-refractory prostate cancer.
Hai-Lei MAO ; Zhi-Qi ZHU ; Charlie Degui CHEN
Asian Journal of Andrology 2009;11(1):69-73
Advanced prostate cancer is responsive to hormone therapy that interferes with androgen receptor (AR) signalling. However, the effect is short-lived, as nearly all tumours progress to a hormone-refractory (HR) state, a lethal stage of the disease. Intuitively, the AR should not be involved because hormone therapy that blocks or reduces AR activity is not effective in treating HR tumours. However, there is still a consensus that AR plays an essential role in HR prostate cancer (HRPC) because AR signalling is still functional in HR tumours. AR signalling can be activated in HR tumours through several mechanisms. First, activation of intracellular signal transduction pathways can sensitize the AR to castrate levels of androgens. Also, mutations in the AR can change AR ligand specificity, thereby allowing it to be activated by non-steroids or anti-androgens. Finally, overexpression of the wild-type AR sensitizes itself to low concentrations of androgens. Therefore, drugs targeting AR signalling could still be effective in treating HRPC.
Androgen Antagonists
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therapeutic use
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Androgens
;
physiology
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Humans
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Ligands
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Male
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Prostatic Neoplasms
;
drug therapy
;
physiopathology
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Receptors, Androgen
;
physiology
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Signal Transduction
;
physiology
3.Bipolar androgen therapy: A novel therapeutic strategy for castration-resistant prostate cancer.
Yong-Hui HU ; Jian-Chao GUO ; Meng ZHANG
National Journal of Andrology 2017;23(12):1138-1140
Bipolar androgen therapy (BAT), as a new therapeutic strategy for castration-resistant prostate cancer (CRPC), can significantly reduce the level of prostate-specific antigen (PSA) for prostate cancer patients and has exhibited an excellent safety profile with no serious adverse events. Based on the clinical trials recently published at home and abroad, this article reviews the background, action mechanism, development, and prospect of BAT.
Androgen Antagonists
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therapeutic use
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Hormone Replacement Therapy
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methods
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Humans
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Male
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Prostate-Specific Antigen
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blood
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Prostatic Neoplasms, Castration-Resistant
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blood
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drug therapy
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Receptors, Androgen
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Testosterone
;
administration & dosage
;
blood
4.FOXA1 in prostate cancer.
Hui-Yu DONG ; Lei DING ; Tian-Ren ZHOU ; Tao YAN ; Jie LI ; Chao LIANG
Asian Journal of Andrology 2023;25(3):287-295
Most prostate cancers initially respond to androgen deprivation therapy (ADT). With the long-term application of ADT, localized prostate cancer will progress to castration-resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), and neuroendocrine prostate cancer (NEPC), and the transcriptional network shifted. Forkhead box protein A1 (FOXA1) may play a key role in this process through multiple mechanisms. To better understand the role of FOXA1 in prostate cancer, we review the interplay among FOXA1-targeted genes, modulators of FOXA1, and FOXA1 with a particular emphasis on androgen receptor (AR) function. Furthermore, we discuss the distinct role of FOXA1 mutations in prostate cancer and clinical significance of FOXA1. We summarize possible regulation pathways of FOXA1 in different stages of prostate cancer. We focus on links between FOXA1 and AR, which may play different roles in various types of prostate cancer. Finally, we discuss FOXA1 mutation and its clinical significance in prostate cancer. FOXA1 regulates the development of prostate cancer through various pathways, and it could be a biomarker for mCRPC and NEPC. Future efforts need to focus on mechanisms underlying mutation of FOXA1 in advanced prostate cancer. We believe that FOXA1 would be a prognostic marker and therapeutic target in prostate cancer.
Humans
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Male
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Androgen Antagonists/therapeutic use*
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Androgens/metabolism*
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Hepatocyte Nuclear Factor 3-alpha/metabolism*
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Mutation
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Prostatic Neoplasms, Castration-Resistant/drug therapy*
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Receptors, Androgen/metabolism*
5.Estrogen receptor beta suppresses the androgen receptor oncogenic effects in triple-negative breast cancer.
Feng XU ; Kun XU ; Lingling FAN ; Xintong LI ; Yiqiu LIU ; Fang YANG ; Chengjun ZHU ; Xiaoxiang GUAN
Chinese Medical Journal 2024;137(3):338-349
BACKGROUND:
Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer associated with poor prognosis and limited treatment options. The androgen receptor (AR) has emerged as a potential therapeutic target for luminal androgen receptor (LAR) TNBC. However, multiple studies have claimed that anti-androgen therapy for AR-positive TNBC only has limited clinical benefits. This study aimed to investigate the role of AR in TNBC and its detailed mechanism.
METHODS:
Immunohistochemistry and TNBC tissue sections were applied to investigate AR and nectin cell adhesion molecule 4 (NECTIN4) expression in TNBC tissues. Then, in vitro and in vivo assays were used to explore the function of AR and estrogen receptor beta (ERβ) in TNBC. Chromatin immunoprecipitation sequencing (ChIP-seq), co-immunoprecipitation (co-IP), molecular docking method, and luciferase reporter assay were performed to identify key molecules that affect the function of AR.
RESULTS:
Based on the TNBC tissue array analysis, we revealed that ERβ and AR were positive in 21.92% (32/146) and 24.66% (36/146) of 146 TNBC samples, respectively, and about 13.70% (20/146) of TNBC patients were ERβ positive and AR positive. We further demonstrated the pro-tumoral effects of AR on TNBC cells, however, the oncogenic biology was significantly suppressed when ERβ transfection in LAR TNBC cell lines but not in AR-negative TNBC. Mechanistically, we identified that NECTIN4 promoter -42 bp to -28 bp was an AR response element, and that ERβ interacted with AR thus impeding the AR-mediated NECTIN4 transcription which promoted epithelial-mesenchymal transition in tumor progression.
CONCLUSIONS
This study suggests that ERβ functions as a suppressor mediating the effect of AR in TNBC prognosis and cell proliferation. Therefore, our current research facilitates a better understanding of the role and mechanisms of AR in TNBC carcinogenesis.
Humans
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Androgens/therapeutic use*
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Estrogen Receptor beta/metabolism*
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Receptors, Androgen/therapeutic use*
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Triple Negative Breast Neoplasms/metabolism*
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Molecular Docking Simulation
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Cell Line, Tumor
6.Impact of taxanes on androgen receptor signaling.
Shanshan BAI ; Bryan Y ZHANG ; Yan DONG
Asian Journal of Andrology 2019;21(3):249-252
The development and progression of metastatic castration-resistant prostate cancer is the major challenge in the treatment of advanced prostate cancer. The androgen receptor signaling pathway remains active in metastatic castration-resistant prostate cancer. Docetaxel and cabazitaxel are the first- and second-line chemotherapy, respectively, for patients with metastatic castration-resistant prostate cancer. These two taxanes, in general, function by (i) inhibiting mitosis and inducing apoptosis and (ii) preventing microtubule-dependent cargo trafficking. In prostate cancer, taxanes have been reported to inhibit the nuclear translocation and activity of the androgen receptor. However, whether this is attainable or not clinically remains controversial. In this review, we will provide a comprehensive view of the effects of taxanes on androgen receptor signaling in prostate cancer.
Antineoplastic Agents, Phytogenic/therapeutic use*
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Humans
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Male
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Prostatic Neoplasms, Castration-Resistant/drug therapy*
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Receptors, Androgen/drug effects*
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Signal Transduction/drug effects*
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Taxoids/therapeutic use*
7.The current status of hormone treatment for prostate cancer patients in Korean real-world practice: a multi-institutional observational study.
Jung Kwon KIM ; Jung Jun KIM ; Taek Won GANG ; Tae Kyun KWON ; Hong Sup KIM ; Seung Chul PARK ; Jae-Shin PARK ; Jong-Yeon PARK ; Seok Joong YOON ; Youn-Soo JEON ; Jin Seon CHO ; Kwan Joong JOO ; Sung-Hoo HONG ; Seok-Soo BYUN
Asian Journal of Andrology 2019;21(2):115-120
We aimed to evaluate the current nationwide trend, efficacy, safety, and quality of life (QoL) profiles of hormone treatment in real-world practice settings for prostate cancer (PCa) patients in Korea. A total of 292 men with any biopsy-proven PCa (TanyNanyMany) from 12 institutions in Korea were included in this multi-institutional, observational study of prospectively collected data. All luteinizing hormone-releasing hormone (LHRH) agonists were allowed to be investigational drugs. Efficacy was defined as (1) the rate of castration (serum testosterone ≤50 ng dl-1) at 4-week visit and (2) breakthrough (serum testosterone >50 ng dl-1 after castration). Safety assessments included routine examinations for potential adverse events, laboratory tests, blood pressure, body weight, and bone mineral density (BMD, at baseline and at the last follow-up visit). QoL was assessed using the Expanded Prostate Cancer Index Composite-26 (EPIC-26). The most common initial therapeutic regimen was LHRH agonist with anti-androgen (78.0%), and the most commonly used LHRH agonist for combination and monotherapy was leuprolide (64.0% for combination and 58.0% for monotherapy). The castration and breakthrough rates were 78.4% and 6.6%, respectively. The laboratory results related to dyslipidemia worsened after 4 weeks of hormone treatment. In addition, the mean BMD T-score was significantly lower at the last follow-up (mean: -1.950) compared to baseline (mean: -0.195). The mean total EPIC-26 score decreased from 84.8 (standard deviation [s.d.]: 12.2) to 78.3 (s.d.: 8.1), with significant deterioration only in the urinary domain (mean: 23.5 at baseline and 21.9 at the 4-week visit). These findings demonstrate the nationwide trend of current practice settings in hormone treatment for PCa in Korea.
Aged
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Androgen Antagonists/therapeutic use*
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Antineoplastic Agents, Hormonal/therapeutic use*
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Cholesterol/blood*
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Drug Therapy, Combination
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Humans
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Leuprolide/therapeutic use*
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Male
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Middle Aged
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Prostatic Neoplasms/pathology*
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Quality of Life
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Receptors, LHRH/agonists*
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Republic of Korea
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Testosterone/blood*
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Treatment Outcome
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Triglycerides/blood*
8.Proliferative response of human prostate cancer cell to hormone inhibited by androgen receptor antisense RNA.
Jun JIANG ; Luo-fu WANG ; Yu-hua FANG ; Feng-shuo JIN ; Wen-sheng JIN
Chinese Medical Journal 2004;117(5):684-688
BACKGROUNDThe failure of endocrine treatment for advanced prostate cancer might be related to aberrant activation of androgen receptor (AR). Prostate cancer cell line LNCaP contains AR that can be activated by androgen, estrogen and progesterone. This study was set to investigate the effects of antisense AR RNA on growth of LNCaP cultured in medium containing varied concentrations of R1881, 17beta-estradiol, and progesterone, respectively.
METHODSLNCaP cells transfected with antisense AR RNA retroviral vector pL-AR-SN were designated as LNCaPas-AR. LNCaP cells containing empty vector pLXSN served as LNCaPNeo. LNCaP and LNCaPNeo were taken as controls. In vitro cell growth assay, proliferative cells of LNCaP and tranfected LNCaPs were counted by typan staining when they cultured with synthetic androgen R1881, 17beta-estradiol, and progesterone, respectively.
RESULTSGrowth of LNCaPas-AR was inhibited significantly (P < 0.05) compared with that of LNCaP and LNCaPNeo at 1 nmol/L R1881, 10 nmol/L 17beta-estradiol, and 1 nmol/L progesterone, respectively. No difference was seen between LNCaP and LNCaPNeo (P > 0.05). Microscopic observation showed that LNCaP and LNCaPNeo cells grew well, but only few LNCaPas-AR cells were alive.
CONCLUSIONSOur observations indicate that antisense AR RNA retroviral vector pL-AR-SN could change androgen-independent characteristics of LNCaP cells, which might shed some novel insights into the treatment of androgen-independent prostate cancer.
Androgen Receptor Antagonists ; Cell Division ; drug effects ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Estradiol ; pharmacology ; Humans ; Male ; Metribolone ; antagonists & inhibitors ; pharmacology ; Progesterone ; antagonists & inhibitors ; pharmacology ; Prostatic Neoplasms ; pathology ; therapy ; RNA, Antisense ; therapeutic use ; Receptors, Androgen ; genetics
9.Effects of extract of Buddleja officinalis eye drops on androgen receptors of lacrimal gland cells of castrated rats with dry eye.
Qing-Hua PENG ; Xiao-Lei YAO ; Quan-Long WU
Chinese Journal of Integrated Traditional and Western Medicine 2012;32(1):72-114
OBJECTIVETo observe the effects of the extract of Buddleja officinalis eye drops (EBOED) on basic tears secretory volume, tear film stability, and expressions of androgen receptors (AR) in castrated rats with dry eye, and to investigate the mechanism of EBOED on dry eye caused by decreased anti-androgen levels.
METHODSForty-five male Wistar rats were randomly divided into the blank group, the model group, and the treatment group (treated by EBOED), respectively. Rats in each group were further divided into three sub-groups (fed for one month, two months, and three months, respectively). There were totally nine groups, with five in each. The dry eye model was established with orchiectomy of rats in the model group and the treatment group. EBOED was given to rats in the treatment group for one successive month. Schirmer I test (SIT) and breakup time of tear film (BUT) were determined in all experimental rats. Expressions of AR was analyzed by flow cytometer.
RESULTSThs SIT value, BUT, and AR positive rate in the model group at the 1st, 2nd, 3rd month were lower than those in the blank group of the same time points (P < 0.01). There was statistical difference in SIT value, BUT, and AR positive rate between the model group and the treatment group at the three time points (P < 0.01). Take the three-month subgroup as an example, the SIT value in the treatment group was (12.667 +/- 5.221) mm, obviously higher than that in the model group (2.676 +/- 1.987) mm. The BUT in the treatment group was (11.758 +/- 4.415) s, obviously longer than that of the model group (4.667 +/- 2.108) s. The AR positive rate in the treatment group was 49.33% +/- 3.44%, obviously higher than that of the model group (33.32% +/- 7.12%, all P < 0.01).
CONCLUSIONSThe main components of EBOED was the flavonoids which could significantly inhibit the occurrence of dry eye in rats with decreased androgen levels. Its mechanism might possibly be similar to androgen.
Animals ; Buddleja ; chemistry ; Dry Eye Syndromes ; drug therapy ; metabolism ; Flavones ; pharmacology ; therapeutic use ; Lacrimal Apparatus ; metabolism ; Male ; Orchiectomy ; Plant Extracts ; pharmacology ; therapeutic use ; Rats ; Rats, Wistar ; Receptors, Androgen ; metabolism
10.Scaffold protein MAPK8IP2 expression is a robust prognostic factor in prostate cancer associated with AR signaling activity.
Jian HUANG ; Wang LIU ; Bi-Yun LIN ; Jean C LI ; Jane LU ; Ben-Yi LI
Asian Journal of Andrology 2023;25(2):198-207
Mitogen-activated protein kinase-8-interacting protein 2 (MAPK8IP2) is a scaffold protein that modulates MAPK signal cascades. Although MAPK pathways were heavily implicated in prostate cancer progression, the regulation of MAPK8IP2 expression in prostate cancer is not yet reported. We assessed MAPK8IP2 gene expression in prostate cancer related to disease progression and patient survival outcomes. MAPK8IP2 expression was analyzed using multiple genome-wide gene expression datasets derived from The Cancer Genome Atlas (TCGA) RNA-sequence project and complementary DNA (cDNA) microarrays. Multivariable Cox regressions and log-rank tests were used to analyze the overall survival outcome and progression-free interval. MAPK8IP2 protein expression was evaluated using the immunohistochemistry approach. The quantitative PCR and Western blot methods analyzed androgen-stimulated MAPK8IP2 expression in LNCaP cells. In primary prostate cancer tissues, MAPK8IP2 mRNA expression levels were significantly higher than those in the case-matched benign prostatic tissues. Increased MAPK8IP2 expression was strongly correlated with late tumor stages, lymph node invasion, residual tumors after surgery, higher Gleason scores, and preoperational serum prostate-specific antigen (PSA) levels. MAPK8IP2 upregulation was significantly associated with worse overall survival outcomes and progression-free intervals. In castration-resistant prostate cancers, MAPK8IP2 expression strongly correlated with androgen receptor (AR) signaling activity. In cell culture-based experiments, MAPK8IP2 expression was stimulated by androgens in AR-positive prostate cancer cells. However, MAPK8IP2 expression was blocked by AR antagonists only in androgen-sensitive LNCaP but not castration-resistant C4-2B and 22RV1 cells. These results indicate that MAPK8IP2 is a robust prognostic factor and therapeutic biomarker for prostate cancer. The potential role of MAPK8IP2 in the castration-resistant progression is under further investigation.
Male
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Humans
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Androgens/therapeutic use*
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Receptors, Androgen/genetics*
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Prognosis
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Mitogen-Activated Protein Kinase 8/therapeutic use*
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Cell Line, Tumor
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Prostatic Neoplasms/pathology*
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Prostatic Neoplasms, Castration-Resistant/drug therapy*
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Gene Expression Regulation, Neoplastic