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1.
Rev. chil. endocrinol. diabetes ; 14(1): 21-28, 2021. ilus, tab
Article in Spanish | LILACS | ID: biblio-1146468

ABSTRACT

El síndrome de insensibilidad a andrógenos (AIS en la sigla inglesa) es una entidad muy poco frecuente en endocrinología. Se caracteriza por la mutación del receptor de andrógenos de magnitud variable, por medio del cual individuos 46,XY no se virilizan normalmente, a pesar de conservar sus testículos y tener concentraciones de testosterona en rango masculino. El cuadro clínico es variable y depende la profundidad de la alteración del receptor. En un extremo, hay casos de insensibilidad androgénica completa (CAIS) con fenotipo femenino. En el otro extremo hay insensibilidad parcial (PAIS) que se extiende desde el fenotipo femenino, con o sin ambigüedad genital, hasta los casos de hombres infértiles o con subvirilización, que presentan insensibilidad androgénica más leve. En los fenotipos femeninos, los testículos suelen estar en posición ectópica y aquellos ubicados dentro del abdomen tienen riesgo de malignizarse, por lo que suelen extirparse. Estos son los casos de más difícil manejo, pues aparte de la necesidad de gonadectomía seguida de terapia hormonal femenina, existe una vagina estrecha y en fondo de saco ciego y que suele requerir corrección quirúrgica para permitir la actividad sexual. En este trabajo presentamos 5 casos de AIS vistos recientemente en 2 centros clínicos de Santiago y que ilustran la heterogeneidad de presentación. Además, hacemos una revisión actualizada de los criterios diagnósticos, los tratamientos más adecuados y el manejo global de esta condición.


The Androgen insensitivity syndrome (AIS, in its English acronym) is a very rare entity in endocrinology. It is characterized by a variable magnitude androgen receptor mutation, whereby 46, XY individuals are not normally virilized, despite retaining their testicles and having testosterone concentrations in the male range. The clinical picture is variable and depends on the depth of the receptor alteration. At one extreme, there are cases of complete androgenic insensitivity (CAIS) with a female phenotype. At the other extreme, there is partial insensitivity (PAIS) that extends from the female phenotype, with or without genital ambiguity, to cases of infertile or undervirilized men, who have milder androgenic insensitivity. In female phenotypes, the testes are usually in an ectopic position and those located within the abdomen are at risk of malignancy, and therefore are usually removed. These are the most difficult cases to manage because apart from the need for gonadectomy followed by female hormonal therapy, there is a narrow vagina and a deep blind pouch that usually requires surgical correction to allow sexual activity. In this work, we present 5 cases of AIS recently seen in 2 clinical centers in Santiago and that illustrate the heterogeneity of presentation. In addition, we make an updated review of the diagnostic criteria, the most appropriate treatments, and the overall management of this condition.


Subject(s)
Humans , Female , Adolescent , Adult , Middle Aged , Young Adult , Androgen-Insensitivity Syndrome/diagnosis , Phenotype , Disorders of Sex Development , Androgen-Insensitivity Syndrome/genetics , Androgen-Insensitivity Syndrome/therapy , Testis , Magnetic Resonance Imaging , Receptors, Androgen , Tomography, X-Ray Computed , Diagnosis, Differential
2.
Protein & Cell ; (12): 29-38, 2021.
Article in English | WPRIM | ID: wpr-880916

ABSTRACT

Prostate cancer is the most commonly diagnosed non-cutaneous cancers in North American men. While androgen deprivation has remained as the cornerstone of prostate cancer treatment, resistance ensues leading to lethal disease. Forkhead box A1 (FOXA1) encodes a pioneer factor that induces open chromatin conformation to allow the binding of other transcription factors. Through direct interactions with the Androgen Receptor (AR), FOXA1 helps to shape AR signaling that drives the growth and survival of normal prostate and prostate cancer cells. FOXA1 also possesses an AR-independent role of regulating epithelial-to-mesenchymal transition (EMT). In prostate cancer, mutations converge onto the coding sequence and cis-regulatory elements (CREs) of FOXA1, leading to functional alterations. In addition, FOXA1 activity in prostate cancer can be modulated post-translationally through various mechanisms such as LSD1-mediated protein demethylation. In this review, we describe the latest discoveries related to the function and regulation of FOXA1 in prostate cancer, pointing to their relevance to guide future clinical interventions.


Subject(s)
Amino Acid Sequence , Epigenesis, Genetic , Epithelial-Mesenchymal Transition , Gene Expression Regulation, Neoplastic , Hepatocyte Nuclear Factor 3-alpha/metabolism , Histone Demethylases/metabolism , Histones/metabolism , Humans , Male , Mutation , Prostate/pathology , Prostatic Neoplasms/pathology , Protein Binding , Protein Processing, Post-Translational , Receptors, Androgen/metabolism , Signal Transduction , Transcription, Genetic
3.
Article in Chinese | WPRIM | ID: wpr-826373

ABSTRACT

Ubiquitin is a small molecule protein consisting of 76 amino acids,widely found in eukaryotic cells. The process by which ubiquitin binding to a specific protein is called ubiquitination. Deubiquitination is the reversed process of ubiquitination. Ubiquitination stimulates downstream signal,including complex assembly,protein conformation and activity changes,proteolysis,autophagy,guilt,chromatin remodeling,and DNA repair. More than 80% of eukaryotic protein degradation is mediated by the ubiquitination system,and ubiquitin-dependent proteolysis is an extremely complex process involving many biomolecular processes. By regulating protein homeostasis,ubiquitination can also regulate a variety of biological processes including cell cycle,cell proliferation,and apoptosis,which are closely related to tumorigenesis and progression. Many abnormalities of androgen receptor (AR) including AR gene amplification,mutation,shear mutation,and AR activity enhancement are closely related to prostate cancer progression. In particular,prostate cancer progression is regulated by the ubiquitination/deubiquitination processes. This article summarizes the recent research advances in the roles of ubiquitination/deubiquitination in AR abnormalities and prostate cancer.


Subject(s)
Cell Line, Tumor , Humans , Male , Prostatic Neoplasms , Metabolism , Pathology , Proteolysis , Receptors, Androgen , Metabolism , Ubiquitination
4.
Clin. biomed. res ; 40(1): 37-43, 2020.
Article in English | LILACS | ID: biblio-1117078

ABSTRACT

Introduction: The androgen receptor (AR) plays an important role in normal development of the prostate gland, as well as in prostatic neoplasms. Transcriptional regulation by AR is modulated by its interaction with co-activators or co-repressors, such as NCoR1 (nuclear receptor co-repressor 1), which is involved in reducing AR activity over the target gene transcription. Methods: To identify the role of NCoR1 in the prostate cancer androgen independence in a cell line model, we aimed to evaluate the effects of silencing NCoR1 on prostate-specific antigen (PSA) gene expression, the proliferative response and PSA secretion on the supernatant of C4-2B and LNCaP cells that were submitted to small interfering RNAs (siRNAs) transfection, and to treatments with different androgen dosages. Results: In LNCaP and C4-2B cells with no dihydrotestosterone (DHT) treatment, a decrease in PSA mRNA expression was observed 48 hours and 72 hours after gene silencing in the siNCoR group when compared to the control and siNC groups. The LNCaP and C4-2B cells showed a biphasic pattern in response to dihydrotestosterone treatment in transfected groups (siNCoR and siNC) as well as in the control condition (without transfection). The secretion of PSA in cell supernatant of LNCaP and C4-2B cells was higher in the siNCoR group, and, in relation to hormonal treatment, higher in the 10-8 M DHT group. Conclusions: A reduction in the NCoR1 levels seems to have a double influence on the activity of AR in PCa cells. These results suggest that NCoR may act as an AR co-repressor depending upon hormonal stimulation.(AU)


Subject(s)
Humans , Male , Prostatic Neoplasms , Prostate-Specific Antigen , Cell Proliferation , Nuclear Receptor Co-Repressor 1 , Dihydrotestosterone , Receptors, Androgen , Cell Line , Co-Repressor Proteins
5.
Med. leg. Costa Rica ; 36(1): 6-13, ene.-mar. 2019.
Article in Spanish | LILACS | ID: biblio-1002552

ABSTRACT

Resumen Se presenta el caso de una femenina de 69 años con un carcinoma ductal in situ de la mama, el cual presentaba diferenciación apocrina y alto grado nuclear. La forma de presentación clínica se hizo patente en forma de microcalcificaciones detectadas en la mamografía, y corroboradas histológicamente como comedonecrosis. La diferenciación apocrina se comprobó por medio de tinciones de inmunohistoquímica. El diagnóstico se realizó en una biopsia excisional, pero dado a que uno de los márgenes se encontraba comprometido, la paciente se sometió posteriormente a una mastectomía.


Abstract We present the case of a 69 year old female diagnosed with a ductal in situ carcinoma of the breast. The tumor had apocrine differentiation and a high nuclear grade. The clinical presentation corresponded to microcalcifications detected on mammography, which were histologically patent in the form of comedo type necrosis. The aforementioned apocrine differentiation was reassured using the aid of immunohistochemistry. The biopsy was an excisional biopsy, but due to positive quirurgical margins, the patient was later reintervened for total mastectomy.


Subject(s)
Humans , Female , Aged , Breast Neoplasms , Receptors, Androgen , Receptors, Progesterone , Receptors, Estrogen , Carcinoma, Ductal, Breast , Costa Rica
6.
Pesqui. vet. bras ; 39(1): 40-46, Jan. 2019. tab, ilus
Article in English | LILACS, VETINDEX | ID: biblio-990239

ABSTRACT

Canine prostate gland is a hormonal dependent organ and its imbalance of estrogen and androgen receptor expressions are directly associated with the development of different diseases. Due to the lack of information regarding the behavior of the aforementioned receptors in canine prostate cancer (PC), this study aimed to identify estrogen receptor alpha (ERα), androgen receptor (AR), Ki67 and phosphatase and tensin homolog (PTEN) protein expressions in canine PC by immunohistochemistry. We found nuclear expression of ERα and AR in the epithelial cells of normal canine samples and a loss of protein expression in PC samples. Normal samples showed Ki67 expression in a few basal cells and the PC samples showed the highest mean of positive cells (253.1). Canine prostate cancer showed a high proliferative index, which was associated with independence of hormonal actuation. PTEN showed positive nuclear and cytoplasmic expression in normal canine samples and a loss in PC. Loss of ERα, AR and PTEN indicated that canine PC exhibits the same immunohistochemical phenotype as in human patients with PC resistant to hormonal therapy. Therefore, canine PC should be considered as a model to study human PC resistant to hormonal therapy.(AU)


A glândula prostática canina é um órgão dependente de hormônio, e o desequilíbrio na expressão dos receptores de estrógeno e andrógeno estão diretamente associados com o desenvolvimento de diferentes doenças. Devido à falta de informação sobre o comportamento desses receptores no câncer prostático canino (PC), este estudo tem por objetivo identificar a expressão proteica através da técnica de imuno-histoquímica do receptor de estrógeno alfa (REα), receptor de andrógeno (RA), Ki67 e fosfatase e tensina homóloga (PTEN). Foi encontrado nas células epiteliais prostáticas normais caninas a expressão nuclear de REα e RA, e perda de expressão proteica nas amostras de PC. As amostras normais apresentaram expressão de Ki67 em poucas células basais e as amostras de PC apresentaram a maior média de células positivas (253,1). O câncer de próstata canino apresentou uma taxa alta de proliferação, o qual foi associado com a atuação independente de hormônio. As amostras de próstatas caninas normais revelaram marcação nuclear e citoplasmática da proteína PTEN e perda nas amostras de PC. A perda de REα, RA e PTEN indicam que as amostras de PC exibem o mesmo fenótipo imuno-histoquímico de pacientes humanos com câncer prostático resistente a terapia hormonal. Sendo assim, o PC canino deve ser considerado um modelo para estudos de câncer prostático humano resistente a terapia hormonal.(AU)


Subject(s)
Animals , Dogs , Prostate/pathology , Prostatic Hyperplasia/veterinary , Prostatic Neoplasms/veterinary , Prostatic Intraepithelial Neoplasia/veterinary , Dogs , Receptors, Androgen , Receptors, Cytoplasmic and Nuclear , Estrogen Receptor alpha , Disease Models, Animal , Prostatic Neoplasms, Castration-Resistant/veterinary
7.
Natural Product Sciences ; : 200-207, 2019.
Article in English | WPRIM | ID: wpr-760572

ABSTRACT

Albizzia julibrissin (AJ) is an herbal medicine that shows low toxicity, promotes promoting blood circulation and mitigates the inflammation and has mild side effects. Benign prostate hyperplasia (BPH) is one of the most common diseases that occurs in older males and often results in lower urinary tract symptoms. This study was conducted to evaluate the protective effect of AJ against BPH using LNCaP cells and Sprague Dawley rats treated with testosterone. Treatment with AJ extract reduced the expression of androgen receptor (AR) and prostate-specific antigen (PSA) in vitro. In vivo, rats were divided into 6 groups: 1 (Normal Control); 2 (Testosterone propionate (TP) alone); 3 (TP + finasteride); 4 (TP + AJ 10 mg/kg); 5 (TP + AJ 50 mg/kg); 6 (TP + AJ 300 mg/kg). The groups treated with AJ showed reduced the relative prostate weights and BPH-related proteins were altered, with decreased AR, PSA and proliferating cell nuclear antigen (PCNA) observed by western blot. Histopathological analysis revealed the therapeutic effect of AJ, with a decreased thickness of epithelial cells and reduced level of PCNA and 5α-reductase type 2. These results suggest that AJ extract could ameliorate testosterone-induced benign prostatic hyperplasia.


Subject(s)
Albizzia , Animals , Blood Circulation , Blotting, Western , Diethylpropion , Epithelial Cells , Herbal Medicine , Humans , Hyperplasia , In Vitro Techniques , Inflammation , Lower Urinary Tract Symptoms , Male , Proliferating Cell Nuclear Antigen , Prostate , Prostate-Specific Antigen , Prostatic Hyperplasia , Rats , Rats, Sprague-Dawley , Receptors, Androgen , Testosterone , Weights and Measures
8.
Article in Chinese | WPRIM | ID: wpr-772007

ABSTRACT

OBJECTIVE@#To detect potential variant of AR gene in an infant with complete androgen insensitivity syndrome.@*METHODS@#The coding regions and splicing sites of the AR gene were subjected to PCR amplification and direct DNA sequencing. Fluorescence quantitative PCR was also used to detect copy number alterations of exons 2 to 8 of the AR gene.@*RESULTS@#Deletion of exons 2 to 8 was detected in the proband, and the results were verified among the family members.@*CONCLUSION@#Hemizygotic deletion of exons 2 to 8 of the AR gene probably underlies the complete androgen insensitivity syndrome in this infant.


Subject(s)
Androgen-Insensitivity Syndrome , Genetics , Base Sequence , Exons , Humans , Infant , Male , Polymerase Chain Reaction , Receptors, Androgen , Genetics
9.
Article in English | WPRIM | ID: wpr-763125

ABSTRACT

PURPOSE: Proline, glutamic acid, and leucine-rich protein 1 (PELP1), a novel nuclear receptor (NR) co-regulator, is highly expressed in breast cancer. We investigated its expression in breast cancer subtypes, in comparison with other breast markers as well as cancers from different sites. Its prognostic relevance with different subtypes and other NR expression was also examined in breast cancers. MATERIALS AND METHODS: Immunohistochemical analysis was performed on totally 1,944 cancers from six different organs. RESULTS: PELP1 expression rate was the highest in breast cancers (70.5%) among different cancers. Compared to GATA3, mammaglobin and gross cystic disease fluid protein 15, PELP1 was less sensitive than GATA3 for luminal cancers, but was the most sensitive for non-luminal cancers. PELP1 has low expression rate (<20%) in colorectal cancers, gastric cancers and renal cell carcinomas, but higher in lung cancers (49.1%) and ovarian cancers (42.3%). In breast cancer, PELP1 expression was an independent adverse prognostic factor for non-luminal cancers (disease-free survival [DFS]: hazard ratio [HR], 1.403; p=0.012 and breast cancer specific survival [BCSS]: HR, 1.443; p=0.015). Interestingly, its expression affected the prognostication of androgen receptor (AR). AR(pos)PELP1(lo) luminal cancer showed the best DFS (log-rank=8.563, p=0.036) while AR(neg)PELP1(hi) non-luminal cancers showed the worst DFS (log-rank=9.536, p=0.023). CONCLUSION: PELP1 is a sensitive marker for breast cancer, particularly non-luminal cases. However, its considerable expression in lung and ovarian cancers may limit its utility in differential diagnosis in some scenarios. PELP1 expression was associated with poor outcome in non-luminal cancers and modified the prognostic effects of AR, suggesting the potential significance of NR co-regulator in prognostication.


Subject(s)
Breast Neoplasms , Breast , Carcinoma, Renal Cell , Colorectal Neoplasms , Diagnosis, Differential , Glutamic Acid , Immunohistochemistry , Lung , Lung Neoplasms , Ovarian Neoplasms , Phenobarbital , Prognosis , Proline , Receptors, Androgen , Stomach Neoplasms
10.
Annals of Dermatology ; : 530-537, 2019.
Article in English | WPRIM | ID: wpr-762376

ABSTRACT

BACKGROUND: Androgenic alopecia (AGA) is the most common type of hair loss. It is likely inherited genetically and is promoted by dihydrotestosterone. 5α-reductase has been proven a good target through finasteride use. However, the pathogenesis of AGA cannot be fully explained based only on dihydrotestosterone levels. OBJECTIVE: To identify similar hairloss inhibition activity of RE-ORGA with mode of action other than finasteride. METHODS: We prepared RE-ORGA from Korean herb mixtures. We performed MTT assays for cytotoxicity, Cell Counting Kit-8 assays for cell proliferation, and western blot to identify expression levels of 5α-reductase and Bax. RNA-sequencing was performed for the expression patterns of genes in dihydrotestosterone-activated pathways. Anti-inflammatory activity was also assessed by the expression levels of tumor necrosis factor-alpha (TNF-α) and interleukin 6. RESULTS: REORGA could promote the proliferation of human dermal papilla cells and showed low cytotoxicity. It also inhibited the expression of 5α-reductases and Bax in the cells. RNA-sequencing results verified that the mRNA expressions of SRD5A1, Bax, transforming growth factor-beta 1 (TGF-β1), and TGF-β1 induced transcript 1 (TGFβ1I1) were decreased, whereas expression of protein tyrosine kinase 2 beta (PTK2β) was more elevated. REORGA also showed anti-inflammatory activity through decreased mRNA levels of TNF-α. CONCLUSION: Transcriptionally, up-regulation of PTK2β and concomitant down-regulation of TGFβ1I1 imply that RE-ORGA can modulate androgen receptor sensitivity, decreasing the expression of 5α-reductase type II and Bax together with TGF-β1 transcripts; RE-ORGA also showed partial anti-inflammatory activity. Overall, RE-ORGA is expected to alleviate hair loss by regulating 5α-reductase activity and the receptor's androgen sensitivity.


Subject(s)
Alopecia , Blotting, Western , Cell Count , Cell Proliferation , Cholestenone 5 alpha-Reductase , Dihydrotestosterone , Down-Regulation , Finasteride , Hair , Humans , Interleukin-6 , Protein-Tyrosine Kinases , Receptors, Androgen , RNA, Messenger , Tumor Necrosis Factor-alpha , Up-Regulation
11.
Article in English | WPRIM | ID: wpr-761887

ABSTRACT

Androgen receptor (AR) is a steroid receptor transcriptional factor for testosterone and dihydrotestosterone consisting of four main domains, the N-terminal domain, DNA-binding domain, hinge region, and ligand-binding domain. AR plays pivotal roles in prostate cancer, especially castration-resistant prostate cancer (CRPC). Androgen deprivation therapy can suppress hormone-naïve prostate cancer, but prostate cancer changes AR and adapts to survive under castration levels of androgen. These mechanisms include AR point mutations, AR overexpression, changes of androgen biosynthesis, constitutively active AR splice variants without ligand binding, and changes of androgen cofactors. Studies of AR in CRPC revealed that AR was still active in CRPC, and it remains as a potential target to treat CRPC. Enzalutamide is a second-generation antiandrogen effective in patients with CRPC before and after taxane-based chemotherapy. However, CRPC is still incurable and can develop drug resistance. Understanding the mechanisms of this resistance can enable new-generation therapies for CRPC. Several promising new AR-targeted therapies have been developed. Apalutamide is a new Food and Drug Administration-approved androgen agonist binding to the ligand-binding domain, and clinical trials of other new AR-targeted agents binding to the ligand-binding domain or N-terminal domain are underway. This review focuses on the functions of AR in prostate cancer and the development of CRPC and promising new agents against CRPC.


Subject(s)
Androgen Antagonists , Castration , Dihydrotestosterone , Drug Resistance , Drug Therapy , Humans , Point Mutation , Prostate , Prostatic Neoplasms , Receptors, Androgen , Receptors, Steroid , Testosterone
12.
Article in English | WPRIM | ID: wpr-719629

ABSTRACT

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.


Subject(s)
Blotting, Western , Castration , Eosine Yellowish-(YS) , Hematoxylin , Humans , Immunohistochemistry , Male , Passive Cutaneous Anaphylaxis , Prostate , Prostatectomy , Prostatic Hyperplasia , Prostatic Neoplasms , Real-Time Polymerase Chain Reaction , Receptors, Androgen , Recurrence , RNA, Messenger , Tissue Banks
13.
Article in English | WPRIM | ID: wpr-719624

ABSTRACT

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.


Subject(s)
Aging , Animals , Blotting, Western , Epididymis , Hypogonadism , Male , Models, Animal , Oxidative Stress , Phytotherapy , Prescriptions , Rats , Rats, Sprague-Dawley , Receptors, Androgen , Superoxide Dismutase , Testis , Testosterone , Water , Weights and Measures
14.
Article in English | WPRIM | ID: wpr-786128

ABSTRACT

BACKGROUND: The worldwide incidence of squamous cell carcinoma of the tongue (SCCOT) in young patients has been increasing. We investigated clinicopathologic features of this unique population and compared them with those of SCCOT in the elderly to delineate its pathogenesis.METHODS: We compared clinicopathological parameters between patients under and over 45 years old. Immunohistochemical assays of estrogen receptor, progesterone receptor, androgen receptor, p53, p16, mdm2, cyclin D1, and glutathione S-transferase P1 were also compared between them.RESULTS: Among 189 cases, 51 patients (27.0%) were under 45 years of age. A higher proportion of women was seen in the young group, but was not statistically significant. Smoking and drinking behaviors between age groups were similar. Histopathological and immunohistochemical analysis showed no significant difference by age and sex other than higher histologic grades observed in young patients.CONCLUSIONS: SCCOT in young adults has similar clinicopathological features to that in the elderly, suggesting that both progress via similar pathogenetic pathways.


Subject(s)
Aged , Carcinoma, Squamous Cell , Cyclin D1 , Drinking , Drinking Behavior , Epithelial Cells , Estrogens , Female , Glutathione Transferase , Humans , Immunohistochemistry , Incidence , Mouth Neoplasms , Receptors, Androgen , Receptors, Progesterone , Smoke , Smoking , Tongue , Young Adult
15.
Journal of Breast Cancer ; : 141-148, 2019.
Article in English | WPRIM | ID: wpr-738408

ABSTRACT

The luteinizing hormone-releasing hormone/androgen receptor (LHRH/AR) pathway is a promising treatment target in a subgroup of female patients with triple-negative breast cancer (TNBC). However, very little is known about the efficacy of this strategy in male patients with TNBC. In this report, we describe a male patient with AR-positive TNBC who was successfully treated using an LHRH agonist after pretreatment with several lines of chemotherapy and achieved a durable response. We also review the existing evidence supporting LHRH- and AR-targeted therapy for this rare disease.


Subject(s)
Breast Neoplasms, Male , Drug Therapy , Female , Gonadotropin-Releasing Hormone , Goserelin , Humans , Lutein , Male , Male , Rare Diseases , Receptors, Androgen , Triple Negative Breast Neoplasms
16.
National Journal of Andrology ; (12): 116-121, 2018.
Article in Chinese | WPRIM | ID: wpr-775210

ABSTRACT

Objective@#To establish enzalutamide-resistant human prostate cancer cell lines and screen out the lncRNA and mRNA expression profiles associated with enzalutamide resistance.@*METHODS@#Human prostate cancer cell lines LNCAP and C4-2B were cultured with 10 μmol/L enzalutamide for 6 months in vitro for the establishment of enzalutamide-resistant subclones LNCAP-ENZA and C4-2B-ENZA. The IC50 value and enzalutamide resistance index of each cell line were examined by MTT assay, the expressions of enzalutamide-related genes FL-AR, AR-V7 and HnRNPA1 were determined by Western blot, and the lncRNA and mRNA differential expressions of C4-2B and C4-2B-ENZA were detected by high-throughout lncRNA microarray.@*RESULTS@#Compared with LNCAP and C4-2B, the IC50 values of enzalutamide-resistant subclones LNCAP-ENZA (60.83 μmol/L) and C4-2B-ENZA (88.32 μmol/L) were increased significantly (P < 0.05) and the enzalutamide-resistance indexes of the LNCAP-ENZA and C4-2B-ENZA cells were 4.94 and 4.67, respectively. The expressions of AR-V7 and HnRNPA1 were markedly up-regulated in the LNCAP-ENZA and C4-2B-ENZA cells as compared with those in the LNCAP and C4-2B cells, but that of FL-AR showed no significant change. A total of 1 440 lncRNAs and 1 236 mRNAs were identified as differentially expressed in the C4-2B-ENZA cells.@*CONCLUSIONS@#Enzalutamide -resistant human prostate cancer cell subclones LNCAP-ENZA and C4-2B-ENZA were successfully established and enzalutamide resistance-associated lncRNA and mRNA were identified, which may provide some molecular evidence for the management of enzalutamide-resistant human prostate cancer.


Subject(s)
Cell Line, Tumor , Drug Resistance, Neoplasm , Humans , Male , Phenylthiohydantoin , Pharmacology , Prostatic Neoplasms , Drug Therapy , Genetics , Pathology , RNA, Long Noncoding , Metabolism , RNA, Messenger , Metabolism , RNA, Neoplasm , Metabolism , Receptors, Androgen
17.
Article in English | WPRIM | ID: wpr-772963

ABSTRACT

Androgen receptor (AR) is a ligand-activated transcription factor that plays a pivotal role in the development and progression of many severe diseases such as prostate cancer, muscle atrophy, and osteoporosis. Binding of ligands to AR triggers the conformational changes in AR that may affect the recruitment of coactivators and downstream response of AR signaling pathway. Therefore, AR ligands have great potential to treat these diseases. In this study, we searched for novel AR ligands by performing a docking-based virtual screening (VS) on the basis of the crystal structure of the AR ligand binding domain (LBD) in complex with its agonist. A total of 58 structurally diverse compounds were selected and subjected to LBD affinity assay, with five of them (HBP1-3, HBP1-17, HBP1-38, HBP1-51, and HBP1-58) exhibiting strong binding to AR-LBD. The IC values of HBP1-51 and HBP1-58 are 3.96 µM and 4.92 µM, respectively, which are even lower than that of enzalutamide (Enz, IC = 13.87 µM), a marketed second-generation AR antagonist. Further bioactivity assays suggest that HBP1-51 is an AR agonist, whereas HBP1-58 is an AR antagonist. In addition, molecular dynamics (MD) simulations and principal components analysis (PCA) were carried out to reveal the binding principle of the newly-identified AR ligands toward AR. Our modeling results indicate that the conformational changes of helix 12 induced by the bindings of antagonist and agonist are visibly different. In summary, the current study provides a highly efficient way to discover novel AR ligands, which could serve as the starting point for development of new therapeutics for AR-related diseases.


Subject(s)
Androgen Receptor Antagonists , Pharmacology , Androgens , Metabolism , Pharmacology , Biological Assay , Cell Line, Tumor , Drug Discovery , Methods , Humans , Ligands , Male , Molecular Docking Simulation , Molecular Dynamics Simulation , Phenylthiohydantoin , Pharmacology , Principal Component Analysis , Prostatic Neoplasms , Drug Therapy , Protein Binding , Physiology , Protein Conformation , Receptors, Androgen , Metabolism
18.
Article in English | WPRIM | ID: wpr-719219

ABSTRACT

Androgen insensitivity syndrome (AIS) is a rare genetic disease caused by various abnormalities in the androgen receptor (AR). The AR is an essential steroid hormone receptor that plays a critical role in male sexual differentiation and development and preservation of the male phenotype. Mutations in the AR gene on the X chromosome cause malfunction of the AR so that a 46,XY karyotype male has some physical characteristics of a woman or a full female phenotype. Depending on the phenotype, AIS can be classified as complete, partial or mild. Here, we report 2 cases of complete AIS in young children who showed complete sex reversal from male to female as a result of AR mutations. They had palpable inguinal masses and normal female external genitalia, a blind-end vagina and absent Müllerian duct derivatives. They were both 46,XY karyotype and AR gene analysis demonstrated pathologic mutations in both. Because AIS is inherited in an X-linked recessive manner, we performed genetic analysis of the female family members of each patient and found the same mutation in the mothers of both patients and in the female sibling of case 2. Gonadectomy was performed in both patients to avoid the risk of malignancy in the undescended testicles, and estrogen replacement therapy is planned for their adolescence. Individuals with complete AIS are usually raised as females and need appropriate care.


Subject(s)
Adolescent , Androgen-Insensitivity Syndrome , Child , Disorders of Sex Development , Estrogen Replacement Therapy , Female , Genitalia , Humans , Karyotype , Male , Mothers , Phenotype , Receptors, Androgen , Sex Differentiation , Siblings , Testis , Vagina , X Chromosome
19.
Article in English | WPRIM | ID: wpr-717727

ABSTRACT

BACKGROUND/OBJECTIVES: Benign prostatic hypertrophy (BPH) is a major cause of abnormal overgrowth of the prostate mainly in the elderly. Corni Fructus has been reported to be effective in the prevention and treatment of various diseases because of its strong antioxidant effect, but its efficacy against BPH is not yet known. This study was designed to evaluate the therapeutic efficacy of Corni Fructus water extract (CF) in testosterone-induced BPH rats. MATERIALS/METHODS: To induce BPH, rats were intraperitoneal injected with testosterone propionate (TP). Rats in the treatment group were orally administered with CF with TP injection, and finasteride, which is a selective inhibitor of 5α-reductase type 2, was used as a positive control. RESULTS: Our results showed that the increased prostate weight and histopathological changes in BPH model rats were suppressed by CF treatment. CF, similar to the finasteride-treated group, decreased the levels of testosterone and dihydrotestosterone by TP treatment in the serum, and it also reduced 5α-reductase expression and concentration in prostate tissue and serum, respectively. In addition, CF significantly blocked the expression of the androgen receptor (AR), AR co-activators, and proliferating cell nuclear antigen in BPH rats, and this blocking was associated with a decrease in prostate-specific antigen levels in serum and prostate tissue. CONCLUSIONS: These results suggest that CF may weaken the BPH status through the inactivation of at least 5α-reductase and AR activity and may be useful for the clinical treatment of BPH.


Subject(s)
Aged , Animals , Antioxidants , Cornus , Dihydrotestosterone , Finasteride , Humans , Proliferating Cell Nuclear Antigen , Prostate , Prostate-Specific Antigen , Prostatic Hyperplasia , Rats , Receptors, Androgen , Testosterone , Testosterone Propionate , Water
20.
Article in English | WPRIM | ID: wpr-715777

ABSTRACT

BACKGROUND: Lung cancer in never smokers (LCINS) differs etiologically and clinically from lung cancer attributed to smoking. After smoking, radon exposure is the second leading cause and the primary risk factor of lung cancer among never smokers. Exposure to radon can lead to genetic and epigenetic alterations in tumor genomes affecting genes and pathways involved in lung cancer development. The present study sought to explore genetic alterations associated with LCINS exposed to radon gas indoors. METHODS: Genetic associations were assessed via a case-control study of LCINS (39 cases and 30 controls) using next generation sequencing. Associations between genetic mutations and high exposure to radon were investigated by OncoPrint and heatmap graphs. Bioinformatic analysis was conducted using various tools. According radon exposure levels, we divided subjects in two groups of cases and controls. RESULTS: We found that ABL2 rs117218074, SMARCA4 rs2288845, PIK3R2 rs142933317, MAPK1 rs1803545, and androgen receptor (AR) rs66766400 were associated with LCINS exposed to high radon levels. Among these, Chromodomain helicase DNA-binding protein 4 (CHD4) rs74790047, TSC2 rs2121870, and AR rs66766408 were identified as common exonic mutations in both lung cancer patients and normal individuals exposed to high levels of radon indoor. CONCLUSION: We identified that CHD4 rs74790047, TSC2 rs2121870, and AR rs66766408 are found to be common exonic mutations in both lung cancer patients and normal individuals exposed to radon indoors. Further analysis is needed to determine whether these genes are completely responsible for LCINS exposed to residential radon.


Subject(s)
Case-Control Studies , Computational Biology , Epigenomics , Exons , Genetic Variation , Genome , Humans , Lung Neoplasms , Lung , Radon , Receptors, Androgen , Risk Factors , Smoke , Smoking
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