Osteocalcin improves testicular morphology but does not ameliorate testosterone synthesis signaling in azoospermic mice.

Objective: Osteocalcin (OCN) influences spermatogenesis in conjunction with testosterone and estrogen. OCN facilitates the secretion of testosterone by engaging with G protein-coupled receptor class C group 6 member A (GPRC6A) on Leydig cells and with androgen receptors on Sertoli cells. Methods: Adult mice were assigned to the following groups: control; sham I, which received dimethyl sulfoxide for 5 weeks followed by phosphate-buffered saline for 1 month; azoospermia, which was treated with busulfan (40 mg/kg); sham II, which consisted of azoospermic animals that received phosphate-buffered saline for 1 month beginning at the 5-week mark; and the experimental group, which included azoospermic mice treated with OCN (3 ng/g/day) for 1 month. Results: In the mice receiving OCN treatment, immunohistochemical analysis revealed increased expression of androgen receptors and GPRC6A, indicative of enhanced spermatogenesis. Additionally, the expression levels of the cyclic adenosine monophosphate-responsive element binding protein 1, steroidogenic acute regulatory protein, and cytochrome P450 family 11 genes were elevated. However, testosterone levels exhibited no significant differences across groups. Morphometric analysis suggests that OCN may play a crucial role in spermatogenesis, as evidenced by its positive effects on germinal cells and the germinal epithelium in the azoospermia group (p<0.05). Conclusion: We conclude that OCN may serve as a beneficial therapeutic agent for male infertility.

Secondary Cancer after Androgen Deprivation Therapy in Prostate Cancer: A Nationwide Study.

PURPOSE: Androgen signaling is associated with various secondary cancer, which could be promising for potential treatment using androgen deprivation therapy (ADT). This study investigated whether ADT use was associated with secondary cancers other than prostate cancer in a nationwide population-based cohort. MATERIALS AND METHODS: A total, 278,434 men with newly diagnosed prostate cancer between January 1, 2002 and December 31, 2017 were identified. After applying the exclusion criteria, 170,416 men were enrolled. The study cohort was divided into ADT and non-ADT groups by individual matching followed by propensity score matching (PSM). Study outcomes were incidence of all male cancers. Cox proportional hazard regression models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of events. RESULTS: During a median follow-up of 4.5 years, a total of 11,059 deaths (6,329 in the ADT group and 4,730 in the non-ADT group) after PSM were found. After PSM, the overall all-cause of secondary cancer incidence risk of the ADT group was higher than that of the non-ADT group (HR: 1.312, 95% CI: 1.23-1.36; adjusted HR: 1.344, 95% CI: 1.29-1.40). The ADT group showed higher risk of overall brain and other central nervous system (CNS) cancer-specific incidence than the non-ADT group (adjusted HR: 1.648, 95% CI: 1.21-2.24). The ADT group showed lower risks of overall cancer-specific incidence for stomach, colon/rectum, liver/inflammatory bowel disease (IBD), gall bladder/extrahepatic bile duct, lung, bladder, and kidney cancers than the non-ADT group. When the duration of ADT was more than 2 years of ADT, the ADT group showed higher risk of cancer-specific incidence for brain and other CNS cancers but lower risk of cancer-specific incidence for liver/IBD and lung cancers than the non-ADT group. CONCLUSIONS: This study demonstrates that ADT could affect cancer-specific incidence for various cancers.

AKR1C2 Promotes Metastasis and Regulates the Molecular Features of Luminal Androgen Receptor Subtype in Triple Negative Breast Cancer Cells.

PURPOSE: Patients with triple-negative breast cancer (TNBC) have an increased risk of distant metastasis compared to those with other subtypes. In this study, we aimed to identify the genes associated with distant metastasis in TNBC and their underlying mechanisms. METHODS: We established patient-derived xenograft (PDX) models using surgically resected breast cancer tissues from 31 patients with TNBC. Among these, 15 patients subsequently developed distant metastases. Candidate metastasis-associated genes were identified using RNA sequencing. In vitro wound healing, proliferation, migration, and invasion assays and in vivo tumor xenograft and metastasis assays were performed to determine the functional importance of aldo-keto reductase family 1 member C2 (AKR1C2). Additionally, we used the METABRIC dataset to investigate the potential role of AKR1C2 in regulating TNBC subtypes and their downstream signaling activities. RESULTS: RNA sequencing of primary and PDX tumors showed that genes involved in steroid hormone biosynthesis, including AKR1C2, were significantly upregulated in patients who subsequently developed metastasis. In vitro and in vivo assays showed that silencing of AKR1C2 resulted in reduced cell proliferation, migration, invasion, tumor growth, and incidence of lung metastasis. AKR1C2 was upregulated in the luminal androgen receptor (LAR) subtype of TNBC in the METABRIC dataset, and AKR1C2 silencing resulted in the downregulation of LAR classifier genes in TNBC cell lines. The androgen receptor (AR) gene was a downstream mediator of AKR1C2-associated phenotypes in TNBC cells. AKR1C2 expression was associated with gene expression pathways that regulate AR expression, including JAK-STAT signaling or interleukin 6 (IL-6). The levels of phospho-signal transducer and activator of transcription and IL-6, along with secreted IL-6, were significantly downregulated in AKR1C2-silenced TNBC cells. CONCLUSION: Our data indicate that AKR1C2 is an important regulator of cancer growth and metastasis in TNBC and may be a critical determinant of LAR subtype features.

Malignant Apocrine Lesions of the Breast: Multimodality Imaging Findings and Biologic Features.

The apocrine morphology of the breast is observed in a broad pathological spectrum, ranging from benign cysts to invasive carcinomas. However, the number of clinical research investigating malignant apocrine lesions is limited. This study retrospectively reviewed the data of patients with malignant apocrine lesions admitted in a tertiary center between January 2004 and December 2021, based on the radiology-pathology correlation and the recent advances in their status to enhance the therapeutic implications of androgen receptor (AR). Among the 37 patients with lesions, 27 (73.0%) had triple-negative subtypes with predominant AR expression. The radiological features of malignant apocrine lesions did not differ from those of typical invasive ductal carcinoma or ductal carcinoma in situ. This study demonstrated that knowledge on the imaging features of malignant apocrine lesions and their histological basis could enhance the adoption of new targeted therapies in patients with this particular type of breast cancer.

Oncocytoid Variant of High-Grade Salivary Duct Carcinoma: A Potential Diagnostic Pitfall. A Report on Two Patients.

Salivary duct carcinoma (SDC) is an uncommon and aggressive salivary malignancy. The oncocytoid variant of salivary duct carcinoma (OSDC) has only been reported in the English literature once before. Here we detail two new patients. A 71-year-old female presented with a painless enlarging left parotid mass. Imaging and fine-needle aspiration were nondiagnostic. The second patient, a 79-year-old male, presented with painless swelling in the right cheek. Imaging was nondiagnostic. Both patients underwent surgical resection. Histopathology revealed bland yet infiltrative OSDC in both cases. These tumors were AR+ (androgen receptor) by immunohistochemistry. Potential difficulty exists in distinguishing the oncocytoid variant of SDC, a rare and relatively bland tumor, from oncocytoma, a more commonly encountered entity. AR expression can aid in the correct diagnosis.

A triple-negative breast cancer surrogate subtype classification that correlates with gene expression subtypes.

BACKGROUND: This study developed a triple-negative breast cancer (TNBC) surrogate subtype classification that represents TNBC subtypes based on the Vanderbilt subtype classification. METHODS: Patients who underwent primary curative surgery for TNBC were included. Representative FFPE blocks were used for gene expression analysis and tissue microarray construction for immunohistochemical (IHC) staining. The Vanderbilt subtypes were re-classified into four groups: basal-like (BL), mesenchymal-like (M), immunomodulatory (IM) and luminal androgen receptor (LAR) subtype. Classification and regression tree (CART) modeling was applied to develop a surrogate subtype classification. RESULTS: A total of 145 patients were included. The study cohort was allocated to the Vanderbilt 4 subtypes as LAR (n = 22, 15.2%), IM (n = 32, 22.1%), M (n = 38, 26.2%), BL (n = 25, 17.2%) and unclassified (n = 28, 19.3%). After excluding nine (6.2%) patients due to poor IHC staining quality, CART modeling was performed. TNBC surrogate subtypes were defined as follows: LAR subtype, androgen receptor Allred score 8; IM subtype, LAR-negative with a tumor-infiltrating lymphocyte (TIL) score > 70%; M subtype, LAR-negative with a TIL score < 20%; BL subtype, LAR-negative with a TIL score 20-70% and diffuse, strong p16 staining. The study cohort was classified by the surrogate subtypes as LAR (n = 26, 17.9%), IM (n = 21, 14.5%), M (n = 44, 30.3%), BL1 (n = 27, 18.6%) and unclassified (n = 18, 12.4%). Surrogate subtypes predicted TNBC Vanderbilt 4 subtypes with an accuracy of 0.708. CONCLUSION: We have developed a TNBC surrogate subtype classification that correlates with the Vanderbilt subtype. It is a practical and accessible diagnostic test that can be easily applied in clinical practice.

Interleukin-1β mediates the effect of macrophage androgen receptor on hyperphosphate-induced vascular smooth muscle cell calcification / 中华肾脏病杂志

Objective:To investigate whether it is by regulating interleukin 1β ( IL-1β) gene expression that androgen receptor (AR) in macrophages affects hyperphosphate-induced vascular smooth muscle cell calcification. Methods:The chromatin immunoprecipitation (ChIP) experiment was used to determine whether AR was bound to the androgen receptor element (ARE) sequence of IL-1β promoter in THP-1 cells. Whether the AR regulated IL-1β gene expression was detected by luciferase assay experiments. AR of THP-1 cells was silenced and transfected by lentivirus with vector or shRNA. Flow cytometry was used to select positive transfected cells THP-1ARsc (control) and THP-1ARsi (AR silencing) with fluorescent markers. Western blotting was used to detect AR protein levels of THP-1ARsc (control) and THP-1ARsi cells (AR silencing in monocytes). Macrophages MФARsc (control) or MФARsi (AR silencing) were induced by 50 ng/ml phorbol ester. Enzyme-linked immunosorbent assay was used to detect IL-1β expression levels of MФARsc or MФARsi conditioned medium. The human aortic smooth muscle cells (HASMC) were cultured in MФARsc or MФARsi conditioned medium with phosphate (2.5 mmol/L final concentration of sodium dihydrogen phosphate), and Alizarin red S staining was used to analyze HASMC calcification degree. Western blotting was used to detect the expression levels of RUNX2 (osteoblast marker) and SM22α (HASMC marker), and neutralization assay was performed to test IL-1β-mediating effect of macrophages AR on HASMC calcification. Results:AR was bound to ARE sequence of IL-1β promoter and regulated IL-1β gene expression. The expression level of IL-1β protein in conditioned medium of MФARsi cells decreased significantly compared to MФARsc cells ( P<0.001). Compared with MФARsc conditioned medium group, HASMC calcium deposition in MФARsi conditioned medium group decreased significantly, RUNX2 protein decreased and SM22α protein increased (all P<0.05). The degree of HASMC calcification in the MФARsi conditioned medium+IgG antibody group decreased than that in the MФARsc conditioned medium+IgG antibody group significantly, and the degree of HASMC calcification in the MФARsc conditioned medium+IL-1β antibody group decreased significantly than that in the MФARsc conditioned medium+IgG antibody group; while the degree of HASMC calcification in the MФARsi conditioned medium+IgG antibody group and MФARsi conditioned medium+IL-1β antibody group decreased than that in the MФARsc conditioned medium+IL-1β antibody group (all P<0.05). Conclusions:Macrophage AR regulates IL-1β expression by binding to ARE sequence within IL-1β promoter, and IL-1β mediates the effect of macrophage AR on hyperphosphate-induced HASMC calcification.

Effects of Low-to-Moderate Doses of Anabolic Steroids on Lipid Profile and Muscle Hypertrophy in Resistance Training Practitioners: A Systematic Review with Meta-Analysis

Abstract Background: The use of androgenic anabolic steroids (AAS) is prevalent among young bodybuilders, motivated by aesthetic results. Although the medical community condemns this practice for its potential deleterious effect, we must recognize the need for more scientific research on the likelihood and magnitude of the adverse events. Objective: To evaluate whether high-quality, scientific evidence supports that AAS negatively affect lipid profile and promote muscle hypertrophy in resistance training practitioners. Methods: A systematic review of the literature of randomized clinical trials was conducted in the PubMed / Medline, Scielo and Science direct databases. The searches were conducted by two independent researchers by June 2018. A significance level of 5% was considered in the analysis. Results: Six clinical trials involving 170 resistance training practitioners were included. A significant heterogeneity was found in studies evaluating the effects of AAS on lipid profile and muscle hypertrophy (I² = 97, 95 and 91%, respectively), with no significant effects on HDL-cholesterol (-5.62mg/dL, 95%CI −12.10, 0.86, p= 0.09), LDL-cholesterol (7.76 mg/dL, 95%CI −9.70, 25.23, p= 0.57) and muscle hypertrophy (2.44kg 95%CI 0.02, 4.86, p=0.05). Conclusion: Current evidence does not support that low-to-moderate doses of AAS cause serious negative effects on lipid profile or promote muscle hypertrophy in resistance training practitioners.

Effects of Androgen Receptor Inhibition on Kanamycin-Induced Hearing Loss in Rats.

Megalin has been proposed as an endocytic receptor for aminoglycosides as well as estrogen and androgen. We aimed to investigate the otoprotective effects of antiandrogens (flutamide, FM) on kanamycin (KM)-induced hearing loss in rats. Rats were divided into four groups. The KM group was administered KM (20 mg/kg/day) for 5 days, while the FM group received FM (15 mg/kg/day) for 10 days. In the KM + FM group, KM and FM (15 mg/kg/day) were simultaneously injected for 5 days and then FM was injected for 5 days. Auditory brainstem responses were measured. Western blotting and/or quantitative reverse transcriptase-polymerase chain reaction were performed for megalin, cytochrome P450 1A1 (Cyp1a1), Cyp1b1, metallothionein 1A (MT1A), MT2A, tumor necrosis factor (TNF)-α, caspase 3, and cleaved caspase 3. The FM + KM group showed attenuated auditory thresholds when compared with the KM group at 4, 8, 16, and 32 kHz (all p < 0.05). The KM + FM group showed lower megalin and Cyp1b1 levels than the KM group (all p < 0.05). The KM + FM group revealed lower MT1A, TNFα, and caspase 3 protein levels, compared with those in the KM group (all p < 0.05). Androgen receptor inhibition protects against cochlear injuries in KM-induced hearing loss rats by attenuating megalin expression, revealing anti-inflammatory and anti-apoptotic effects.

Prognostic value of PSMA, c-MET and E-cadherin in salivary duct carcinoma.

OBJECTIVES: Salivary duct carcinoma (SDC) is a rare and aggressive subtype of salivary gland cancer. Androgen receptor (AR) (96%) and HER2 (29-46%) expression, and a high propensity for regional lymph node metastases are hallmarks of the disease. We hypothesized that c-MET, E-cadherin, PSMA tumor and PSMA neovascular expression may be prognostic factors in SDC. MATERIALS AND METHODS: Expression levels of these proteins were established on tissue microarrays containing 165 primary SDC tumor specimens. Association with survival was studied with Kaplan-Meier curves, and univariable and multivariable Cox regression models. Furthermore, association with lymph node status, AR and HER2 expression, and gender was studied. RESULTS: We found that patients with high PSMA tumor expression showed a significantly longer overall survival (OS) (median 83 vs. 43 months, P = 0.022), a trend towards a longer DFS (median 51 vs. 22 months, P = 0.094), and significantly reduced hazard ratio for death in the univariable Cox regression model (HR 0.46, P = 0.034). In the multivariable model only a high number of tumor-positive lymph nodes and high age (>80) at diagnosis were prognostic for poor OS. High PSMA tumor expression was also significantly associated with low N-stage (P = 0.001) and expression was higher in women versus men (P = 0.029). High PSMA tumor expression and E-cadherin loss were significantly associated with strong and weak AR-expression, respectively (P = 0.033 and P = 0.007). None of the factors were significantly associated with HER2 expression. CONCLUSION: c-MET, E-cadherin, and tumor and neovascular PSMA expression are no independent prognostic factors in SDC.

Prognostic Role of Androgen Receptor Expression in Surgically Resected Early Breast Cancer Patients.

PURPOSE: Endocrine therapy is a standard treatment for hormone receptor-positive breast cancer, which accounts for 60%-75% of all breast cancer. Hormone receptor positivity is a prognostic and predictive biomarker in breast cancer. Approximately 50%-80% of breast cancer is also positive for androgen receptor (AR), but the prognostic and predictive value of AR expression in breast cancer is controversial. Here, we investigated AR expression and its prognostic value in patients with surgically resected breast cancer in Korea. METHODS: We retrospectively reviewed the medical records of patients who had surgically resected breast cancer to collect AR expression data and other clinicopathological data. The optimal cut-off for AR positivity was determined using a receiver operating characteristic curve analysis. RESULTS: We reviewed 957 patients with surgically resected breast cancer from June 2012 to April 2013. The median follow-up was 62 months, and relapse events occurred in 101 (10.6%) patients. Unlike the cut-off value of 1% or 10% in previous reports, 35% was determined to be best for predicting relapse-free survival (RFS) in this study. At the cut-off value of 35%, 654 (68.4%) patients were AR-positive. AR expression was more prevalent in luminal A (87.6%) and luminal B (73.1%) types than in human epidermal growth factor receptor 2-positive (56.2%) or triple-negative (20.6%) types. AR expression of ≥ 35% was significantly related to longer RFS in a multivariate analysis (hazard ratio, 0.430; 95% confidence interval, 0.260-0.709; p = 0.001). CONCLUSION: We propose a cut-off value of 35% to best predict RFS in patients with surgically resected breast cancer. AR expression was positive in 68.4% of patients, and AR positivity was found to be an independent prognostic factor for longer RFS.

The Impact of Androgen Receptor and Histone Deacetylase 1 Expression on the Prognosis of Ductal Carcinoma In Situ.

PURPOSE: Factors associated with invasive recurrence (REC) of ductal carcinoma in situ (DCIS) are less known. This study was aimed at identifying better biomarkers to predict the prognosis of DCIS. METHODS: RNA extracted from formalin-fixed paraffin-embedded blocks of twenty-four pure DCIS cases was subjected to differential gene expression analysis. The DCIS cases were selected by matching age and estrogen receptor status. Sixteen REC-free and 8 invasive-REC cases with disease-free interval of > 5 years were analyzed. Immunohistochemistry (IHC) staining was used to validate sixty-one independent pure DCIS cases, including invasive-REC (n = 16) and REC-free (n = 45) cases. RESULTS: Eight differentially expressed genes (DEGs) were statistically significant (log 2-fold change [FC] < -1 or > 1 and p < 0.001). Less than ½ fold expression of CUL1, androgen receptor (AR), RPS27A, CTNNB1, MAP3K1, PRKACA, GNG12, MGMT genes was observed in the REC group compared to the no evidence of disease group. AR and histone deacetylase 1 (HDAC1) genes were selected for external validation (AR: log 2-FC - 1.35, p < 0.001, and HDAC1: log 2-FC - 0.774, p < 0.001). External validation showed that the absence of AR and high HDAC1 expression were independent risk factors for invasive REC (hazard ratio [HR], 5.04; 95% confidence interval [CI], 1.24-20.4; p = 0.023 and HR, 3.07; 95% CI, 1.04-9.04; p = 0.042). High nuclear grade 3 was also associated with long-term invasive REC. CONCLUSION: Comparative gene expression analysis of pure DCIS revealed 8 DEGs among recurring cases. External validation with IHC suggested that the absence of AR and overexpression of HDAC1 are associated with a greater risk of long-term invasive REC of pure DCIS.

TGF-BETA IN THE NATURAL HISTORY OF PROSTATE CANCER.

All transforming growth factors beta (TGFß) are cytokines that regulate several cellular functions such as cell growth, differentiation and motility. They may also have a role in immunosuppression. Their role is important for normal prostate development. TGFß is active in the regulation of balance between epithelial cell proliferation and apoptosis through stromal epithelia via the androgen receptor action. TGFß protects and maintains prostate stem cells, an important population necessary for prostate tissue regeneration. However, TGFß is shown to have a contrasting role in prostate tumor genesis. In the early stages of tumor development, TGFß acts as a tumor suppressor, whereas in the later stages, TGFß becomes a tumor promoter by inducing proliferation, invasion and metastasis. In this review, we outline complex interactions that TGFß-mediated signaling has on prostate tumor genesis, focusing on the role of these interactions during the course of prostate cancer and, in particular, during disease progression.

The Expression of Androgen Receptor and Its Variants in Human Prostate Cancer Tissue according to Disease Status, and Its Prognostic Significance.

PURPOSE: To evaluate changes in the expression of androgen receptor (AR) and its variants (ARVs) in human prostate cancer (PCa) tissues according to disease status, and its prognostic significance following radical prostatectomy (RP). MATERIALS AND METHODS: A total of 282 PCa cases were evaluated, which included 252 localized PCa, 8 metastatic castration resistant prostate cancer (CRPC), and 22 benign prostatic hyperplasia (BPH) cases. Samples were collected from patients who underwent RP or transurethral resection and were stored in ethically approved tissue banks. Quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry were performed for AR and ARVs. Each tissue was confirmed as cancerous (greater than 80%) using hematoxylin and eosin staining. AR and ARVs expression was compared according to disease status. The biochemical recurrence free survival (BCRFS) rates in men with localized PCa was analyzed according to AR and ARV7 expression using the Kaplan-Meier curve. RESULTS: Only 58 of the 252 localized PCa were included in the analysis because of insufficient cancer tissue. AR and ARV7 mRNA expression was higher in the CRPC tissue than in the localized PCa tissue (p=0.025, p=0.002, respectively). In localized PCa tissue, high AR mRNA and protein level was associated with a low BCRFS rate (log-ranked, p=0.019, p<0.001, respectively). CONCLUSIONS: Overall AR and ARV7 mRNA expression levels were increased in CRPC tissues compared to localized PCa and BPH tissues. High AR protein and mRNA expression in the tumor tissue may be considered a predictive factor of BCRFS following RP.

Effect of Korean Herbal Formula (Modified Ojayeonjonghwan) on Androgen Receptor Expression in an Aging Rat Model of Late Onset Hypogonadism.

PURPOSE: Testosterone replacement therapy is an effective treatment for late-onset hypogonadism (LOH) despite a few contraindications and side-effects. The aim of this study was to determine whether modified Ojayeonjonghwan (KH-204, Korean herbal formula) improved LOH. KH-204 is a strong antioxidant herbal formula. We evaluated the effect of Korean herbal prescription on androgen receptor (AR) expression in an aged rat model of LOH. MATERIALS AND METHODS: Eighteen-month-old rats were used as aged LOH rat models. Eighteen Sprague-Dawley rats were randomly divided into three equal groups of six animals each and treated with one of the following: 1) normal control group (oral administration with distilled water, n=6), 2) KH-204 200 group (oral administration with 200 mg/kg of KH-204, n=6), and 3) KH-204 400 group (oral administration with 400 mg/kg of KH-204, n=6). After four weeks of treatment (once daily, distilled water or KH-204), serum testosterone levels, changes in testicular and epididymal weight, Western blotting analysis of AR expression and measurement of oxidative stress were examined. RESULTS: Treatment with the herbal formulation KH-204 200 mg/kg and 400 mg/kg (1) increased the weights of testis and epididymis; (2) increased the level of serum testosterone; (3) increased the level of superoxide dismutase and reduced the level of 8-hydroxy-20-deoxyguanosine; and (4) upregulated AR expression in testicular tissue. CONCLUSIONS: KH-204 might be an effective alternative for LOH. It improves antioxidant mechanisms and increases testicular AR expression without side-effects.

Androgen receptor expression and association with clinicopathological features and prognosis in early stage triple-negative breast cancer / 国际外科学杂志

Objective To discuss the androgen receptor (AR expresion and its association with clinicopathological features and prognosis in early stage triple-negative breast cancer patients (TNBC).Methods The present study retrospectively analyzed the clinic data of 1 018 patients with early-stage invasive breast cancer treated at the Breast Disease Center at Peking University First Hospital between January 2014 and December 2016,including 1 011 females and 7 males;the age range was 21 to 92 years,and the median age was 57 years.Patients with TNBC were enrolled,and divided into AR positive group and AR negative group according to the expression of AR.The clinicopathological features were analysed,including menopause status,pathological type,T staging,lymph node involvement,anatomic staging,prognostic staging,Ki-67 index,histological grade,vascular tumor thrombus and neuroinvation,and the correlation between the expression of AR and clinicopathological features,curative effect of neoadjuvant chemotherapy and prognosis were calculated.The Student's t test was used to compare continuous data,the Pearsonx2 test or Fisher exact test was used to compare categorical variables,and the Mann-Whitney U test was used for quantitative data.The Kaplan-Meier method was used to analyze survival status,and comparisons between groups were calculated by the log-rank test.Results This study included 148 TNBC,accounting for 14.5％ of all patients,in which all patients were females,and the median age was 55 years,ranging from 27 years to 75 years.The number of AR-positive TNBC was 59,accounted for 39.9％ of all TNBC patients,and the numbers of AR-negative were 89,accounted for 60.1％.Ki-67 index,histological grade and prognostic stage were significantly different in AR-positive and AR-negative TNBC (P ＜ 0.05).There was no statistically significant difference between AR-positive TNBC and AR-negative TNBC in OS (98.3％ vs 95.4％,P =0.830) or in DFS (91.4％ vs 91.0％,P =0.812).Among TNBC who received neoadjuvant chemotherapy,AR-positive patients showed a lower pCR rate than AR-negative patients (x2 =4.381,P =0.046).Conclusions AR expression is associated with lower respond to neoadjuvant chemotherapy in TNBC.However,the association between AR expression and prognosis in TNBCs was still not clear.

Androgen receptor expression and association with clinicopathological features and prognosis in early stage triple-negative breast cancer / 国际外科学杂志

Objective@#To discuss the androgen receptor (AR) expresion and its association with clinicopathological features and prognosis in early stage triple-negative breast cancer patients (TNBC).@*Methods@#The present study retrospectively analyzed the clinic data of 1 018 patients with early-stage invasive breast cancer treated at the Breast Disease Center at Peking University First Hospital between January 2014 and December 2016, including 1 011 females and 7 males; the age range was 21 to 92 years, and the median age was 57 years. Patients with TNBC were enrolled, and divided into AR positive group and AR negative group according to the expression of AR.The clinicopathological features were analysed, including menopause status, pathological type, T staging, lymph node involvement, anatomic staging, prognostic staging, Ki-67 index, histological grade, vascular tumor thrombus and neuroinvation, and the correlation between the expression of AR and clinicopathological features, curative effect of neoadjuvant chemotherapy and prognosis were calculated. The Student’s t test was used to compare continuous data, the Pearson χ2 test or Fisher exact test was used to compare categorical variables, and the Mann-Whitney U test was used for quantitative data. The Kaplan-Meier method was used to analyze survival status, and comparisons between groups were calculated by the log-rank test.@*Results@#This study included 148 TNBC, accounting for 14.5% of all patients, in which all patients were females, and the median age was 55 years, ranging from 27 years to 75 years. The number of AR-positive TNBC was 59, accounted for 39.9% of all TNBC patients, and the numbers of AR-negative were 89, accounted for 60.1%. Ki-67 index, histological grade and prognostic stage were significantly different in AR-positive and AR-negative TNBC(P<0.05). There was no statistically significant difference between AR-positive TNBC and AR-negative TNBC in OS (98.3% vs 95.4%, P=0.830) or in DFS (91.4% vs 91.0%, P=0.812). Among TNBC who received neoadjuvant chemotherapy, AR-positive patients showed a lower pCR rate than AR-negative patients(χ2=4.381, P=0.046).@*Conclusions@#AR expression is associated with lower respond to neoadjuvant chemotherapy in TNBC. However, the association between AR expression and prognosis in TNBCs was still not clear.

The Expression of Androgen Receptor and Its Variants in Human Prostate Cancer Tissue according to Disease Status, and Its Prognostic Significance

PURPOSE: To evaluate changes in the expression of androgen receptor (AR) and its variants (ARVs) in human prostate cancer (PCa) tissues according to disease status, and its prognostic significance following radical prostatectomy (RP). MATERIALS AND METHODS: A total of 282 PCa cases were evaluated, which included 252 localized PCa, 8 metastatic castration resistant prostate cancer (CRPC), and 22 benign prostatic hyperplasia (BPH) cases. Samples were collected from patients who underwent RP or transurethral resection and were stored in ethically approved tissue banks. Quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry were performed for AR and ARVs. Each tissue was confirmed as cancerous (greater than 80%) using hematoxylin and eosin staining. AR and ARVs expression was compared according to disease status. The biochemical recurrence free survival (BCRFS) rates in men with localized PCa was analyzed according to AR and ARV7 expression using the Kaplan-Meier curve. RESULTS: Only 58 of the 252 localized PCa were included in the analysis because of insufficient cancer tissue. AR and ARV7 mRNA expression was higher in the CRPC tissue than in the localized PCa tissue (p=0.025, p=0.002, respectively). In localized PCa tissue, high AR mRNA and protein level was associated with a low BCRFS rate (log-ranked, p=0.019, p < 0.001, respectively). CONCLUSIONS: Overall AR and ARV7 mRNA expression levels were increased in CRPC tissues compared to localized PCa and BPH tissues. High AR protein and mRNA expression in the tumor tissue may be considered a predictive factor of BCRFS following RP.

Effect of Korean Herbal Formula (Modified Ojayeonjonghwan) on Androgen Receptor Expression in an Aging Rat Model of Late Onset Hypogonadism

PURPOSE: Testosterone replacement therapy is an effective treatment for late-onset hypogonadism (LOH) despite a few contraindications and side-effects. The aim of this study was to determine whether modified Ojayeonjonghwan (KH-204, Korean herbal formula) improved LOH. KH-204 is a strong antioxidant herbal formula. We evaluated the effect of Korean herbal prescription on androgen receptor (AR) expression in an aged rat model of LOH. MATERIALS AND METHODS: Eighteen-month-old rats were used as aged LOH rat models. Eighteen Sprague-Dawley rats were randomly divided into three equal groups of six animals each and treated with one of the following: 1) normal control group (oral administration with distilled water, n=6), 2) KH-204 200 group (oral administration with 200 mg/kg of KH-204, n=6), and 3) KH-204 400 group (oral administration with 400 mg/kg of KH-204, n=6). After four weeks of treatment (once daily, distilled water or KH-204), serum testosterone levels, changes in testicular and epididymal weight, Western blotting analysis of AR expression and measurement of oxidative stress were examined. RESULTS: Treatment with the herbal formulation KH-204 200 mg/kg and 400 mg/kg (1) increased the weights of testis and epididymis; (2) increased the level of serum testosterone; (3) increased the level of superoxide dismutase and reduced the level of 8-hydroxy-20-deoxyguanosine; and (4) upregulated AR expression in testicular tissue. CONCLUSIONS: KH-204 might be an effective alternative for LOH. It improves antioxidant mechanisms and increases testicular AR expression without side-effects.

Positive Correlation between Androgen Receptor CAG Repeat Length and Metabolic Syndrome in a Korean Male Population.

PURPOSE: In epidemiological studies, there are various associations of androgen receptor (AR) CAG with several diseases or phenotypes. However, the relationship between CAG repeat length and metabolic syndrome (MS) remains unclear, especially in Asian populations. This study was designed to evaluate the relationship between AR CAG repeat length polymorphism and MS in a Korean male population. MATERIALS AND METHODS: We explored the relationship between AR CAG repeat length polymorphism and MS in a Korean male population (n=337) from 2013 to 2014. AR CAG repeat were determined by microsatellite fragment sizing. Components of MS and laboratory data (lipid profile, fasting glucose, and glycated hemoglobin (HbA1c)) were analyzed with AR CAG repeat length. RESULTS: The mean AR CAG repeat length was 22.3±4.7. Sixty-nine men (20.5%) were diagnosed with MS. Men with MS showed significantly longer AR CAG repeat lengths compared with men without MS (26.2 vs. 21.4, p<0.001). With increasing CAG repeat, the number of components meeting the NCEP criteria increased significantly. AR CAG repeat length was associated significantly with high density lipoprotein (HDL), triglyceride, and HbA1c levels. In the multivariate analysis, CAG repeat length, waist circumference, and levels of HDL were independently associated with MS. (odds ratio (OR)=1.37, 1.19 and 0.90, p<0.001, 0.045, and 0.001, respectively). CONCLUSIONS: AR CAG repeat length was associated with MS and laboratory test results, such as those for HDL, triglycerides, and HbA1c, in Korean males. Longer CAG repeat length was identified as a risk factor for MS in Korean males.