RESUMO
BACKGROUND: Direct evidence for the relationship between a large prostate (≥80 ml) and androgen receptor/PSA signal remains lacking in benign prostatic hyperplasia (BPH). Our aim is to identify whether the cause of a large prostate is related to progesterone receptor (PGR) androgen receptor (AR), oestrogen receptor α, ß (ERα,ß) and prostate-specific antigen (PSA). MATERIALS AND METHODS: Surgical specimens of BPH in plasmakinetic resection of the prostate (PKRP) with three groups of different prostate-sizes with mean volumes of 25.97 ml, 63.80 ml, and 122.37 ml were collected for immunohistochemical analysis of the tissue microarray with PGR, AR, PSA and ERs. Rats were castrated and treated with testosterone replacement to explore androgen and PGR, AR and ERs expression levels in the prostate. Quantitative real-time reverse transcription polymerase chain reaction (Rt-PCR) for mRNA detection of above genes was conducted. RESULTS: Immunoblotting, Rt-PCR and immunohistochemistry assays showed that PGR, PSA, AR, ERα expression levels were positively correlated with prostate size and that ERß expression levels were negatively correlated with prostate volume. Animal experiments have shown that prostate volume is decreased in castrated rats with decreased PGR, AR, ERα and increased ERß expression levels. CONCLUSION: PGR, AR, ERs signals can be regarded as important factors for large-sized prostates in BPH patients (≥100 ml).
Assuntos
Modelos Animais de Doenças , Receptor alfa de Estrogênio , Antígeno Prostático Específico , Próstata , Hiperplasia Prostática , Receptores Androgênicos , Receptores de Progesterona , Masculino , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Animais , Receptores Androgênicos/metabolismo , Receptores de Progesterona/metabolismo , Receptores de Progesterona/análise , Ratos , Humanos , Antígeno Prostático Específico/sangue , Idoso , Receptor alfa de Estrogênio/metabolismo , Receptor alfa de Estrogênio/análise , Próstata/metabolismo , Próstata/patologia , Ratos Sprague-Dawley , Pessoa de Meia-Idade , Receptores de Estrogênio/metabolismo , Receptores de Estrogênio/análise , Receptor beta de Estrogênio/metabolismo , Receptor beta de Estrogênio/análise , Tamanho do ÓrgãoRESUMO
Estradiol and progesterone have been recognized as important mediators of reproductive events in the female mainly via binding to their receptors. This study aimed to characterize the immunolocalization of the estrogen receptor alfa (ERα), estrogen receptor beta (ERß) and progesterone receptor (PR) in the ovarian follicles of the lizard Sceloporus torquatus. The localization of steroid receptors has a spatio-temporal pattern that depends on the stage of follicular development. The immunostaining intensity of the three receptors was high in the pyriform cells and the cortex of the oocyte of previtellogenic follicles. During the vitellogenic phase, the granulosa and theca immunostaining was intense even with the modification of the follicular layer. In the preovulatory follicles, the receptors were found in yolk and additionally, ERα was also located in the theca. These observations suggest a role for sex steroids in regulating follicular development in lizards, like other vertebrates.
Assuntos
Receptor alfa de Estrogênio , Lagartos , Animais , Feminino , Receptor alfa de Estrogênio/análise , Receptor alfa de Estrogênio/metabolismo , Lagartos/metabolismo , Folículo Ovariano/metabolismo , Oócitos/metabolismo , Receptor beta de Estrogênio/análise , Receptor beta de Estrogênio/metabolismo , Estradiol/farmacologia , Estradiol/metabolismo , Células da Granulosa/metabolismoRESUMO
AIM: The aim of this study was to identify the biological characteristics and potential roles of endometrial progenitor cells in the pathogenesis of endometriosis. BACKGROUND: It is generally believed that progenitor cells in human endometrium are responsible for rapid endometrial regeneration. However, the biological characteristics and potential roles of the paired eutopic and ectopic endometrial progenitor cells in endometriosis remain unclear. OBJECTIVE: This study intends to isolate the epithelial progenitor (EP) cells and endometrial mesenchymal stem cells (eMSCs) from the eutopic and ectopic endometria from endometriosis patients, further to reveal their features and functions respectively. METHODS: The distributions of EP cells and eMSCs and the expression of steroid hormone receptors in the endometrium and endometriotic tissues were assessed by immunohistochemistry. EP cells and eMSCs were sorted from paired eutopic and ectopic endometria with epithelial cell adhesion molecule (EpCAM) magnetic beads. The clonogenicity, cell viability after being treated with estradiol and progesterone, and cell markers expression were evaluated with colony forming on Matrigel, CCK-8 and immunofluorescence staining, respectively. The differentially expressed genes (DEGs) were further identified with RNA sequencing. RESULTS: SSEA-1- and PDGFRß-positive cells were distributed in the epithelial and stromal layers. The ERß staining was much more intense in endometriotic tissues, but PR expression was almost absent. The ectopic EP cells exhibit strong clonogenicity and ERß expression but weak PR expression, leading to progesterone resistance. There are 12604 and 13242 DEGs revealed by RNA sequencing between eutopic and ectopic EP cells or eMSCs. GO and KEGG analyses revealed that the functions and pathways of DEGs enriched in cellular energy metabolism and regulation of the immune response, respectively. Additionally, ERß targets were mainly enriched in ectopic EP cells. CONCLUSION: Both EP cells and eMSCs may engage in ectopic lesion formation in endometriosis by modifying the metabolic mode and immune tolerance. These data not only help to understand the molecular mechanism of endometriosis but also could potentially contribute to the discovery of therapeutic targets for endometriosis.
Assuntos
Endometriose , Doenças Uterinas , Feminino , Humanos , Endometriose/etiologia , Endometriose/metabolismo , Endometriose/patologia , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/análise , Receptor beta de Estrogênio/metabolismo , Endométrio , Doenças Uterinas/complicações , Doenças Uterinas/metabolismo , Doenças Uterinas/patologia , Células-Tronco/metabolismoRESUMO
High-mobility group box 2 (HMGB2) is a chromatin-associated protein that is an important regulator of gene transcription, recombination, and repair processes. The functional importance of HMGB2 has been reported in various organs, including the testis, heart, and cartilage. However, its role in the ovary is largely unknown. In this study, ovary tissues from wild-type (WT) and HMGB2-knock-out (KO) mice were examined by histopathological staining and immunohistochemistry. The ovary size and weight were significantly lower in HMGB2-KO mice than in age-matched WT littermates. Histopathological analysis revealed ovarian atrophy and progressive fibrosis in 10-month-old HMGB2-KO mouse ovaries. Compared to age-matched WT mice, the numbers of oocytes and developing follicles were significantly decreased at 2 months of age and were completely depleted at 10 months of age in HMGB2-KO mice. Immunohistochemistry revealed the expression of HMGB2 in the granulosa cells of developing follicles, oocytes, some corpora lutea, and stromal cells. Importantly, HMGB2-positive cells were co-localized with estrogen receptor beta (ERß), but not ERα. Estrogen response element-binding activity was demonstrated by southwestern histochemistry, and it was decreased in HMGB2-KO mouse ovaries. Cell proliferation activity was also decreased in HMGB2-KO mouse ovaries in parallel with the decreased folliculogenesis. These results indicated that the depletion of HMGB2 induced ovarian atrophy that was characterized by a decreased ovarian size and weight, progressive fibrosis, as well as decreased oocytes and folliculogenesis. In conclusion, we demonstrated the crucial role of HMGB2 in mouse ovarian folliculogenesis through ERß expression.
Assuntos
Receptor beta de Estrogênio , Proteína HMGB2 , Animais , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/análise , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Feminino , Células da Granulosa , Proteína HMGB2/análise , Proteína HMGB2/genética , Proteína HMGB2/metabolismo , Camundongos , Camundongos Knockout , Ovário/metabolismoRESUMO
BACKGROUND: Testing for antibodies against podocyte phospholipase A2 receptor-1 (PLA2R) allows clinicians to accurately identify primary membranous nephropathy (MN). Secondary MN is associated with a spectrum of pathology including solid organ malignancy. PLA2R positivity in these patients occurs, although no case of PLA2R-positive MN has been definitively linked to cancer. CASE PRESENTATION: We describe a case of biopsy-proven PLA2R-positive MN, in whom invasive ductal carcinoma of the breast was discovered. The patient underwent surgery and adjuvant chemotherapy (including cyclophosphamide) and went into a sustained complete remission of her nephrotic syndrome. DISCUSSION AND CONCLUSIONS: Case series have reported PLA2R positivity in patients with solid organ malignancy associated MN. Our case is unusual as it is a breast malignancy, and the patients nephrotic syndrome and anti-PLA2Rab titres improved with treatment of the cancer. Here we report, to the best of our knowledge, the first case of oestrogen receptor-2 positive breast cancer associated with PLA2R positive MN in a young lady that was treated successfully by treating the malignancy.
Assuntos
Autoanticorpos/sangue , Neoplasias da Mama/complicações , Glomerulonefrite Membranosa/complicações , Receptores da Fosfolipase A2/imunologia , Adulto , Receptor beta de Estrogênio/análise , Feminino , Glomerulonefrite Membranosa/imunologia , Humanos , Rim/patologiaRESUMO
The rapid decline of circulating 17ß-estradiol (E2) at menopause leads to negative neurological consequences, although hormone therapy paradoxically has both harmful and positive effects depending on the age at which it is delivered. The inconsistent response to E2 suggests unappreciated regulatory mechanisms for estrogen receptors (ERs), and we predicted it could be due to age-related differences in ERß phosphorylation. We assessed ERß phosphorylation using a sensitive mass spectrometry approach that provides absolute quantification (AQUA-MS) of individually phosphorylated residues. Specifically, we quantified phosphorylated ERß in the hippocampus of women (aged 21-83 years) and in a rat model of menopause at 4 residues with conserved sequence homology between the 2 species: S105, S176, S200, and Y488. Phosphorylation at these sites, which spanned all domains of ERß, were remarkably consistent between the 2 species, showing high levels of S105 phosphorylation (80%-100%) and low levels of S200 (20%-40%). Further, S200 phosphorylation decreased with aging in humans and loss of E2 in rats. Surprisingly, Y488 phosphorylation, which has been linked to ERß ligand-independent actions, exhibited approximately 70% phosphorylation, unaltered by species, age, or E2, suggesting ERß's primary mode of action may not require E2 binding. We further show phosphorylation at 2 sites directly altered ERß DNA-binding efficiency, and thus could affect its transcription factor activity. These findings provide the first absolute quantification of ERß phosphorylation in the human and rat brain, novel insights into ERß regulation, and a critical foundation for providing more targeted therapeutic options for menopause in the future.
Assuntos
Receptor beta de Estrogênio/análise , Hipocampo/química , Menopausa/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/metabolismo , Envelhecimento/patologia , Aminoácidos/análise , Aminoácidos/metabolismo , Animais , Estradiol/análise , Estradiol/metabolismo , Receptor beta de Estrogênio/metabolismo , Feminino , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Pessoa de Meia-Idade , Modelos Animais , Fragmentos de Peptídeos/análise , Fragmentos de Peptídeos/metabolismo , Fosforilação , Ratos , Ratos Endogâmicos F344 , Adulto JovemRESUMO
OBJECTIVES: Prior studies have demonstrated that signaling via the estrogen and progesterone receptors (ER and PR) may affect prognosis in non-small cell lung cancer (NSCLC). The precise impact of hormone signaling on clinical outcomes in NSCLC, especially in the context of immune checkpoint blockade, remains unclear. MATERIALS AND METHODS: We obtained RNA-Seq data from The Cancer Genome Atlas (TCGA) to determine mRNA expression levels of ESR1 (ER-α), ESR2 (ER-ß), PGR (PR), CYP19A1 (aromatase), and immune-related genes. Tumor infiltration by activated T cells was predicted based on expression of immune metagenes. RESULTS: High levels of both ESR1 and PGR were associated with significantly decreased tumor infiltration by CD4+ and CD8+ activated T cells. CYP19A1 expression was associated with decreased CD4+ but not CD8+ T cell infiltration. There were no significant differences based on ESR2. These findings persisted after stratifying patients based on sex and tumor histology. In addition, increased ESR1 was associated with high gene expression of immune checkpoint markers, while increased PGR was associated with high levels of TGF-ß genes. In a multivariate logistic regression analysis, ESR1, PGR, TGFB1, and the total number of somatic variants were identified as independent factors predicting T cell infiltration. CONCLUSIONS: Increased gene expression of ER-α and PR was associated with decreased activated T cell infiltration in patients with NSCLC. The relevance of hormone receptor status should be validated clinically, including in the context of immune checkpoint inhibitors.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Receptor alfa de Estrogênio/genética , Neoplasias Pulmonares/genética , Receptores de Progesterona/genética , Linfócitos T/imunologia , Idoso , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Conjuntos de Dados como Assunto , Receptor alfa de Estrogênio/análise , Receptor beta de Estrogênio/análise , Receptor beta de Estrogênio/genética , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Proteínas de Checkpoint Imunológico/análise , Proteínas de Checkpoint Imunológico/genética , Estimativa de Kaplan-Meier , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , RNA-Seq , Receptores de Progesterona/análise , Linfócitos T/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
OBJECTIVE: To identify the risk factors associated with dysmenorrhea in adenomyosis and to discuss the potential hormone-based understanding of pain mechanisms. STUDY DESIGN: Adenomyosis patients with mild or no dysmenorrhea (n = 40, Group 1) and moderate-to-severe dysmenorrhea (n = 80, Group 2) were recruited. Charts of all patients were recorded. An immunohistochemistry (IHC) analysis was performed to detect the cellular levels of estrogen receptor-α (ER-α), estrogen receptor-ß (ER-ß), gonadotropin-releasing hormone receptor (GnRH-R), and neurofilaments (NFs) in 60 cases. RESULTS: A history of cesarean section (CS) was positively related to the degree of dysmenorrhea in adenomyosis (OR (95 % CI): 4.397 (1.371-14.104)). The ER-α levels in the eutopic endometrium (EUE) of Group 2 were higher than those in the ectopic endometrium (ECE) of Group 1. Group 2 had higher NF levels in the ECE than in the EUE. CONCLUSION: A history of CS is a risk factor for adenomyosis with moderate-to-severe dysmenorrhea. For patients with adenomyosis, high ER-α levels in the EUE and high NF levels in the ECE may be related to moderate-to-severe dysmenorrhea. These hormone-based mechanisms may contribute to our understanding of the pathogenesis of dysmenorrhea in adenomyosis.
Assuntos
Adenomiose/epidemiologia , Dismenorreia/epidemiologia , Adenomiose/etiologia , Adenomiose/metabolismo , Adulto , Cesárea/efeitos adversos , Cesárea/estatística & dados numéricos , Dismenorreia/etiologia , Endométrio/química , Endométrio/patologia , Receptor alfa de Estrogênio/análise , Receptor beta de Estrogênio/análise , Feminino , Humanos , Imuno-Histoquímica , Filamentos Intermediários/patologia , Pessoa de Meia-Idade , Gravidez , Receptores LHRH/análise , Fatores de RiscoRESUMO
Within the hypothalamic paraventricular nucleus (PVN), estrogen receptor (ER) ß and other gonadal hormone receptors play a role in central cardiovascular processes. However, the influence of sex and age on the cellular and subcellular relationships of ERß with ERα, G-protein ER (GPER1), as well as progestin and androgen receptors (PR and AR) in the PVN is uncertain. In young (2- to 3-month-old) females and males, ERß-enhanced green fluorescent protein (EGFP) containing neurons were approximately four times greater than ERα-labeled and PR-labeled nuclei in the PVN. In subdivisions of the PVN, young females, compared to males, had: (1) more ERß-EGFP neurons in neuroendocrine rostral regions; (2) fewer ERα-labeled nuclei in neuroendocrine and autonomic projecting medial subregions; and (3) more ERα-labeled nuclei in an autonomic projecting caudal region. In contrast, young males, compared to females, had approximately 20 times more AR-labeled nuclei, which often colocalized with ERß-EGFP in neuroendocrine (approximately 70%) and autonomic (approximately 50%) projecting subregions. Ultrastructurally, in soma and dendrites, PVN ERß-EGFP colocalized primarily with extranuclear AR (approximately 85% soma) and GPER1 (approximately 70% soma). Aged (12- to 24-month-old) males had more ERß-EGFP neurons in a rostral neuroendocrine subregion compared to aged females and females with accelerated ovarian failure (AOF) and in a caudal autonomic subregion compared to post-AOF females. Late-aged (18- to 24-month-old) females compared to early-aged (12- to 14-month-old) females and AOF females had fewer AR-labeled nuclei in neuroendrocrine and autonomic projecting subregions. These findings indicate that gonadal steroids may directly and indirectly influence PVN neurons via nuclear and extranuclear gonadal hormone receptors in a sex-specific manner.
Assuntos
Receptor beta de Estrogênio/biossíntese , Hormônios Esteroides Gonadais/biossíntese , Neurônios/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Caracteres Sexuais , Fatores Etários , Animais , Receptor beta de Estrogênio/análise , Receptor beta de Estrogênio/ultraestrutura , Feminino , Hormônios Esteroides Gonadais/análise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/ultraestrutura , Núcleo Hipotalâmico Paraventricular/química , Núcleo Hipotalâmico Paraventricular/ultraestrutura , Receptores Androgênicos/análise , Receptores Androgênicos/biossíntese , Receptores Androgênicos/ultraestrutura , Receptores Acoplados a Proteínas G/análise , Receptores Acoplados a Proteínas G/biossíntese , Receptores Acoplados a Proteínas G/ultraestruturaRESUMO
Given the high incidence and excellent prognosis of many papillary thyroid microcarcinomas, the Porto proposal uses the designation papillary microtumor (PMT) for papillary microcarcinomas (PMCs) without risk factors to minimize overtreatment and patients' stress. To validate Porto proposal criteria, we examined a series of 190 PMC series, also studying sex hormone receptors and BRAF mutation. Our updated Porto proposal (uPp) reclassifies as PMT incidental PMCs found at thyroidectomy lacking the following criteria: (a) detected under the age of 19 years; (b) with multiple tumors measuring >1 cm adding up all diameters; and (c) with aggressive morphologic features (extrathyroidal extension, angioinvasion, tall, and/or hobnail cells). PMCs not fulfilling uPp criteria were considered "true" PMCs. A total of 102 PMCs were subclassified as PMT, 88 as PMC, with no age or sex differences between subgroups. Total thyroidectomy and iodine-131 therapy were significantly more common in PMC. After a median follow-up of 9.6 years, lymph node metastases, distant metastases, and mortality were only found in the PMC subgroup. No subgroup differences were found in calcifications or desmoplasia. Expression of estrogen receptor-α and estrogen receptor-ß, progesterone receptor, and androgen receptor was higher in PMC than in nontumorous thyroid tissue. BRAF mutations were detected in 44.7% of PMC, with no differences between subgroups. In surgical specimens, the uPp is a safe pathology tool to identify those PMC with extremely low malignant potential. This terminology could reduce psychological stress associated with cancer diagnosis, avoid overtreatment, and be incorporated into daily pathologic practice.
Assuntos
Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Carcinoma Papilar/química , Carcinoma Papilar/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Receptores de Esteroides/análise , Neoplasias da Glândula Tireoide/química , Neoplasias da Glândula Tireoide/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Papilar/patologia , Carcinoma Papilar/terapia , Análise Mutacional de DNA , Receptor alfa de Estrogênio/análise , Receptor beta de Estrogênio/análise , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Radioterapia Adjuvante , Receptores Androgênicos/análise , Receptores de Progesterona/análise , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores Sexuais , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/terapia , Tireoidectomia , Resultado do Tratamento , Adulto JovemRESUMO
AIMS: Characterising the factors responsible for metastatic triple-negative breast cancer (TNBC) is of significant importance, considering its high mortality rate and scant data. In this study, we evaluated the characteristics, clinical behaviour and role of biomarkers (androgen receptor (AR), oestrogen receptor beta (ERß) and p53) in metastatic TNBC. METHODS: Immunohistochemistry was performed for AR, ERß and p53 on 125 primary TNBCs with known metastasis and correlated with clinicopathological parameters and outcome. AR and p53 mRNA profiling was also carried out on 34 tumours from the same series and correlated with outcomes. RESULTS: In this cohort, grade 3 and pT2 tumours predominated. The most common site for metastasis was the lung and pleura (41, 32.8%), and 15 (12.0%) cases demonstrated metastasis in multiple sites. Among these, 92% of tumours metastasised without preceding local recurrences. Five- and ten-year overall survival (OS) rates were 27% and 7.2%, while 5- and 10- year survival rates after metastasis were 9.6% and 3.2% respectively. AR, ERß and p53 protein expressions were observed in 16%, 96.8% and 58.1% of tumours, respectively. A combinational phenotype of AR-ERß+p53+ tumours was associated with poorer OS (HR 1.543, 95%CI 1.030 to 2.310, p=0.035). Higher AR mRNA levels were significantly associated with favourable OS (p=0.015) and survival after metastasis (p=0.027). CONCLUSIONS: Metastatic TNBC harboured aggressive behaviour and displayed predominantly visceral metastasis with most metastatic events occurring without intervening local recurrences. A combinational phenotype of AR-ERß+p53+ was significantly associated with poorer OS.
Assuntos
Biomarcadores Tumorais/análise , Receptor beta de Estrogênio/análise , Receptores Androgênicos/análise , Neoplasias de Mama Triplo Negativas/química , Proteína Supressora de Tumor p53/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Prognóstico , Receptores Androgênicos/genética , Fatores de Tempo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Proteína Supressora de Tumor p53/genéticaRESUMO
Supplementation with phytoestrogens and insoluble fibers has been reported to reduce duodenal polyps in colectomized familial adenomatous polyposis patients, with a mechanism involving, at least in part, upregulation of estrogen receptor-ß subtype, whose expression is lowered during intestinal tumorigenesis. These data suggest a protective effect also in the colon, the main target organ for tumorigenesis in familial adenomatous polyposis and a major cancer type in non-familial (sporadic) cancers. Therefore, we tested whether a similar preparation might reduce tumorigenesis in the colon of Pirc rats (F344/NTac-Apc) mutated in the Apc gene and thus, like familial adenomatous polyposis patients, spontaneously developing multiple tumors in the colon. We first demonstrate that estrogen receptor-ß expression in Pirc rat colon is significantly down-regulated compared to age-matched wt rats. Then, Pirc rats aged 1 month were treated for 3 months with Adipol (Adi), a patented preparation containing phytoestrogens and insoluble fibers. Colon tumorigenesis was significantly reduced by Adi treatment (colon tumors/rat were 5.3 ± 0.8 and 2.9 ± 0.3, Mucin Depleted Foci/rat 127 ± 6.6 and 97.1 ± 8.6 in Controls and Adi-treated rats, respectively, means ± SE, P < 0.01). The treatment also normalized colon proliferation pattern along the crypt and significantly increased apoptosis in colon tumors. Estrogen receptor-ß expression was increased by Adi treatment, especially in the tumors. These positive effects suggest that Adipol may be exploited as a chemopreventive agent to reduce cancer risk in familial adenomatous polyposis patients and to postpone prophylactic colectomy. Moreover, given the similarities between familial adenomatous polyposis and sporadic colorectal cancer, it might also be used as chemopreventive agent in colorectal cancer patients at risk.
Assuntos
Polipose Adenomatosa do Colo/dietoterapia , Carcinogênese/efeitos dos fármacos , Neoplasias do Colo/prevenção & controle , Fibras na Dieta/administração & dosagem , Fitoestrógenos/administração & dosagem , Polipose Adenomatosa do Colo/complicações , Polipose Adenomatosa do Colo/genética , Proteína da Polipose Adenomatosa do Colo/genética , Animais , Apoptose/efeitos dos fármacos , Carcinogênese/genética , Colo/efeitos dos fármacos , Colo/patologia , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Suplementos Nutricionais , Modelos Animais de Doenças , Receptor beta de Estrogênio/análise , Receptor beta de Estrogênio/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Masculino , Mutação , Ratos , Ratos TransgênicosRESUMO
Immunohistochemistry using formalin-fixed, paraffin-embedded tissue, chromogen label, and light microscopy has traditionally been used to semiquantify estrogen receptor (ER) to guide diagnosis and management of breast cancer. Quantitation of ER for this purpose currently only assesses levels of the ER-alpha subtype. Considerable variability in results reported has been due to protocol and fixation variability, intraobserver and interobserver variability, and different scoring systems and thresholds for scoring ER positivity. Results can also vary with low expression levels of ER. ER-beta expression is reduced in breast and ovarian cancers and requires quantitation.Herein we describe a novel approach to quantifying ERß using older mouse ovarian surface epithelium, where ERß is expressed at lower levels than ERα and is therefore harder to detect. We use an antibody highly specific to the ERß1 isoform, together with immunofluorescence, confocal microscopy, and imaging and statistical software to achieve clear, reproducible, and unbiased quantitation of ERß.
Assuntos
Receptor beta de Estrogênio/análise , Regulação da Expressão Gênica , Imuno-Histoquímica/métodos , Microscopia Confocal/métodos , Ovário/metabolismo , Epitélio/metabolismo , Receptor beta de Estrogênio/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Microscopia Intravital/métodos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismoRESUMO
Many women experience some skin reaction or trouble in their monthly menstrual cycle, including the exacerbation of pre-existing diseases and skin eruptions directly associated with sex hormones. We herein report a Japanese woman who experienced repeated systemic urticaria in her premenstrual period, and was diagnosed as having estrogen dermatitis based on a positive result of intradermal estrogen skin test. Of note, the expression of estrogen receptor-ß was increased in small dermal vessels of this case as well as in those of patients with other inflammatory skin diseases. These results suggest that inflammation may induce estrogen receptor-ß expression in small dermal vessels, which potentially modifies the pathological skin inflammation during the menstrual period, leading to the development of estrogen dermatitis.
Assuntos
Dermatite/imunologia , Receptor beta de Estrogênio/metabolismo , Estrogênios/imunologia , Ciclo Menstrual/imunologia , Urticária/imunologia , Dermatite/diagnóstico , Dermatite/patologia , Receptor beta de Estrogênio/análise , Estrogênios/metabolismo , Feminino , Humanos , Testes Intradérmicos/métodos , Pessoa de Meia-Idade , Pele/patologia , Urticária/diagnóstico , Urticária/patologiaRESUMO
Salivary duct carcinoma (SDC) is an aggressive neoplasm that resembles high-grade invasive ductal carcinoma of the breast. It can develop de novo or from the malignant transformation of pleomorphic adenoma (PA). We performed immunohistochemical stains for phosphatase and tensin homologue [PTEN androgen receptor (AR)], HER2/neu, cytokeratin 5/6, estrogen receptor-beta, high-mobility group AT-hook 2 (HMGA2), and pleomorphic adenoma gene 1 (PLAG1) on tissue microarray samples of 75 SDCs and 31 adenocarcinomas, not otherwise specified (NOS). Our data showed the following in SDC samples: loss of PTEN was found in 17 of 60 (28.3%); AR was expressed in 43 of 62 (69.4%); HER2/neu was overexpressed in 25 of 58 (43.1%); cytokeratin 5/6 was expressed in 14 of 54 (25.9%); estrogen receptor-beta was expressed in 37 of 56 (66.1%); HMGA2 was expressed in 29 of 63 (46.0%); and PLAG1 was expressed in 0 of 62 (0%). In addition, there was no statistically significant difference in the age at onset between patients with HMGA2-positive SDCs (range 32-85 years; mean: 64.3 years; median: 64.5 years) and those with HMGA2-negative SDCs (range 41-79 years; mean: 62.5 years; median: 64.5 years). There was also no statistically significant difference in overall survival between patients with HMGA2-positive and HMGA2-negative SDCs (follow-up period range 3-201 months; mean: 49.8 months; median: 30 months). Among 10 patients with a definite PA component (SDC ex-PA), 6 were positive and 4 were negative for HMGA2. Our data were consistent with previous findings that AR and estrogen receptor-beta are expressed in most SDCs, whereas HER2/neu overexpression and loss of PTEN are expressed in a subset of SDCs. In our cohort of patients, HMGA2 was expressed in approximately half of SDCs. HMGA2 and PTEN are promising therapeutic targets for salivary gland tumors.
Assuntos
Biomarcadores Tumorais/análise , Carcinoma Ductal/diagnóstico , Neoplasias das Glândulas Salivares/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal/metabolismo , Carcinoma Ductal/patologia , Proteínas de Ligação a DNA/análise , Proteínas de Ligação a DNA/biossíntese , Receptor beta de Estrogênio/análise , Receptor beta de Estrogênio/biossíntese , Feminino , Proteína HMGA2/análise , Proteína HMGA2/biossíntese , Humanos , Queratina-5/análise , Queratina-5/biossíntese , Queratina-6/análise , Queratina-6/biossíntese , Masculino , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/análise , PTEN Fosfo-Hidrolase/biossíntese , Receptor ErbB-2/análise , Receptor ErbB-2/biossíntese , Receptores Androgênicos/análise , Receptores Androgênicos/biossíntese , Neoplasias das Glândulas Salivares/metabolismo , Neoplasias das Glândulas Salivares/patologiaRESUMO
Renal cell carcinoma (RCC) has the third highest mortality rate among urological tumors, and 20-30% of RCC patients present with metastatic RCC at the time of diagnosis. Although recent studies have indicated that estrogen receptor ß (ERß) could play promoting roles in RCC progression, the detailed mechanisms remain to be clarified. In the present study, we found that expression of ERß, but not ERα, increases with tumor stage and grade, and also observed that modification of ERß signals using estrogens/anti-estrogens, shRNA knockdown of ERß and overexpression of ERß using ectopic cDNA affects RCC cell proliferation, migration and invasion. Mechanism analysis revealed that ERß can promote RCC cell invasion via an increase in transforming growth factor ß1 (TGF-ß1)/SMAD3 signals, and interrupting TGF-ß1/SMAD3 signals with a TGFßR1 inhibitor can reverse/block ERß-increased RCC cell migration. Importantly, preclinical analyses using in vivo mouse models of RCC revealed that targeting of this newly identified ERß/TGF-ß1/SMAD3 pathway with either the FDA-approved anti-estrogen ICI182,780 (Faslodex) or a selective ERß antagonist 4-[2-phenyl-5,7 bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol can significantly reduce RCC tumor growth and invasion, which may be suitable as the basis for novel therapies to more effectively suppress metastatic RCC.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Receptor beta de Estrogênio/metabolismo , Fulvestranto/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Antagonistas do Receptor de Estrogênio/uso terapêutico , Receptor beta de Estrogênio/análise , Receptor beta de Estrogênio/antagonistas & inibidores , Feminino , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Masculino , Camundongos , Camundongos Nus , Terapia de Alvo Molecular , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3/análise , Taxa de Sobrevida , Fator de Crescimento Transformador beta1/análiseRESUMO
Becker's naevus is androgen-dependent. The aim of this study was to investigate whether oestrogen and progesterone receptors are involved in this disorder. Immunohistochemistry showed that epidermal expression of androgen receptors, oestrogen receptors (α, ß) and progesterone receptors was higher in skin lesions of Becker's naevus than in perilesional and control skin. Androgen receptor overexpression was observed in pilosebaceous glands, while oestrogen and progesterone receptor overexpression was seen in hair follicles, but not in sebaceous glands in skin lesions compared with perilesional skin. Reverse tran-scription PCR and Western blot revealed that levels of androgen, oestrogen and progesterone receptors were generally upregulated in skin lesions compared with perilesional and control skin, and their expression was usually higher in perilesional than in control skin. These results suggest that simultaneous overexpression of androgen, oestrogen and progesterone receptors might be implicated in the pathogenesis of Becker's naevus.
Assuntos
Receptor alfa de Estrogênio/análise , Receptor beta de Estrogênio/análise , Nevo/química , Receptores Androgênicos/análise , Receptores de Progesterona/análise , Neoplasias Cutâneas/química , Adolescente , Adulto , Western Blotting , Criança , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Feminino , Humanos , Imuno-Histoquímica , Masculino , Nevo/genética , Nevo/patologia , Receptores Androgênicos/genética , Receptores de Progesterona/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Regulação para Cima , Adulto JovemRESUMO
Testosterone is often recommended in the treatment of several aging-related conditions. However, there are still questions about the consequences of this therapy in terms of hormonal and inflammatory parameters that are crucial for prostate homeostasis. Thus, we investigate if the testosterone therapy (TT) modulates the hormone receptors and inflammatory cytokines in the ventral prostate of adult rats. Wistar rats aging 150 days were divided into two experimental groups (n = 10/group): T: received subcutaneous injections of testosterone cypionate (5 mg/kg body weight) diluted in corn oil every other day for 4 weeks; and C: received corn oil as vehicle. Animals were euthanized at 180 days old by decapitation. Blood was collected to obtain hormone and cytokines concentrations. The ventral prostate was dissected and processed for light microscope and molecular analyses. Relative ventral prostate weight and epithelial compartment were increased after TT. The number of intact and degranulated mast cells was reduced in the T group. Plasma testosterone, DHT and intraprostatic testosterone concentrations were higher in the T group. TT leads to an increase in cell proliferation and up-regulation of AR, ERß, PAR-4, and NRF2. Importantly, plasma concentration and tissue expression of IL-10 and TNF-α were higher after TT. In summary, these results indicate that TT can regulate inflammatory response, with impacts in cytokines and mast cell population, and modulates steroids receptors, important parameters for prostatic homeostasis.
Assuntos
Próstata/efeitos dos fármacos , Testosterona/análogos & derivados , Animais , Proteínas Reguladoras de Apoptose/análise , Proteínas Reguladoras de Apoptose/sangue , Proliferação de Células/efeitos dos fármacos , Citocinas/análise , Citocinas/sangue , Receptor beta de Estrogênio/análise , Receptor beta de Estrogênio/sangue , Inflamação/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/análise , Fator 2 Relacionado a NF-E2/sangue , Próstata/metabolismo , Ratos , Ratos Wistar , Receptores Androgênicos/metabolismo , Testosterona/metabolismo , Testosterona/farmacologiaRESUMO
Oestrogens play an important role in the development and progression of papillary thyroid carcinoma (PTC) through oestrogen receptor (ER)-α and -ß, which may exert different or even opposing actions in PTC. The roles of ERß in ERα-negative PTC are still not clear. This study investigated the expression dynamics of ERß1 (wild-type ERß) and its clinical significance in female ERα-negative PTC patients. ERß1 expression was detected in thyroid tissues of 136 female patients diagnosed with PTC. The relationships between ERß1 expression and clinicopathological/biological factors were also analysed in female ERα-negative PTC patients. The total score for ERß1 was significantly lower in female ERα-negative PTC patients with LNM or ETE when compared to those without LNM or ETE (Z = -2.923, P = 0.003 and Z = -3.441, P = 0.001). Accordingly, the total score for ERß1 was significantly higher in ERα-negative PTC patients expressing E-cadherin compared to patients negative for E-cadherin expression (Z = -2.636, P = 0.008). The total score was lower in ERα-negative PTC patients positive for VEGF expression compared to those negative for VEGF expression (Z = -1.914, P = 0.056). This preliminary study indicates that reduced expression of ERß1 in female ERα-negative PTC patients is associated with greater progression of the disease. This may provide insights into the underlying molecular mechanisms of ERß1 and could help design targeted approaches for treating or even preventing this disease.
Assuntos
Biomarcadores Tumorais/análise , Carcinoma Papilar/química , Movimento Celular , Receptor alfa de Estrogênio/análise , Receptor beta de Estrogênio/análise , Neoplasias da Glândula Tireoide/química , Adolescente , Adulto , Idoso , Carcinoma Papilar/secundário , Progressão da Doença , Regulação para Baixo , Feminino , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Dados Preliminares , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/patologia , Adulto JovemRESUMO
PURPOSE: Numbers of studies have demonstrated that estrogen receptor α and estrogen receptor ß have been involved in development of gastric cancer. Hence, we analyzed studies and The Cancer Genome Atlas (TCGA) data of ERs expression and perform this meta-analysis to access the association between ERα or ER ß and the clinicopathological characteristics, overall survival time, in GC. METHOD: A literature search was performed in PubMed, Cochrane Library, Web of Science, EMBASE database, and Chinese CNKI. Data on the relationship between ERα or ERß expression and clinicopathological features were extracted. A TCGA dataset including information of the ERs expression and clinical data of GC patients was analyzed. Pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. RESULTS: ERα was not associated with cancer risk, lymph node metastasis, infiltration degree, gender, and TNM stage. However, ERß was negatively associated with lymph node metastasis. ERα expression may be associated with poor prognosis in GC patients. CONCLUSION: Estrogen receptors may be related to the progression and deterioration of gastric cancer. However, further high-quality studies are needed to provide more reliable evidence.