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Chinese Medical Journal ; (24): 338-349, 2024.
Article in English | WPRIM | ID: wpr-1007738


BACKGROUND@#Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer associated with poor prognosis and limited treatment options. The androgen receptor (AR) has emerged as a potential therapeutic target for luminal androgen receptor (LAR) TNBC. However, multiple studies have claimed that anti-androgen therapy for AR-positive TNBC only has limited clinical benefits. This study aimed to investigate the role of AR in TNBC and its detailed mechanism.@*METHODS@#Immunohistochemistry and TNBC tissue sections were applied to investigate AR and nectin cell adhesion molecule 4 (NECTIN4) expression in TNBC tissues. Then, in vitro and in vivo assays were used to explore the function of AR and estrogen receptor beta (ERβ) in TNBC. Chromatin immunoprecipitation sequencing (ChIP-seq), co-immunoprecipitation (co-IP), molecular docking method, and luciferase reporter assay were performed to identify key molecules that affect the function of AR.@*RESULTS@#Based on the TNBC tissue array analysis, we revealed that ERβ and AR were positive in 21.92% (32/146) and 24.66% (36/146) of 146 TNBC samples, respectively, and about 13.70% (20/146) of TNBC patients were ERβ positive and AR positive. We further demonstrated the pro-tumoral effects of AR on TNBC cells, however, the oncogenic biology was significantly suppressed when ERβ transfection in LAR TNBC cell lines but not in AR-negative TNBC. Mechanistically, we identified that NECTIN4 promoter -42 bp to -28 bp was an AR response element, and that ERβ interacted with AR thus impeding the AR-mediated NECTIN4 transcription which promoted epithelial-mesenchymal transition in tumor progression.@*CONCLUSIONS@#This study suggests that ERβ functions as a suppressor mediating the effect of AR in TNBC prognosis and cell proliferation. Therefore, our current research facilitates a better understanding of the role and mechanisms of AR in TNBC carcinogenesis.

Humans , Androgens/therapeutic use , Estrogen Receptor beta/metabolism , Receptors, Androgen/therapeutic use , Triple Negative Breast Neoplasms/metabolism , Molecular Docking Simulation , Cell Line, Tumor
Braz. j. med. biol. res ; 50(3): e6057, 2017. tab, graf
Article in English | LILACS | ID: biblio-839271


Ovarian cancer is one of the most common malignancies in women. Semaphorin 4D (sema 4D) is involved in the progress of multiple cancers. In the presence of estrogen-like ligands, estrogen receptors (ERα and ERβ) participate in the progress of breast and ovarian cancers by transcriptional regulation. The aim of the study was to investigate the role of sema 4D and elucidate the regulatory pattern of ERα and ERβ on sema 4D expression in ovarian cancers. Sema 4D levels were up-regulated in ovarian cancer SKOV-3 cells. Patients with malignant ovarian cancers had significantly higher sema 4D levels than controls, suggesting an oncogene role of sema 4D in ovarian cancer. ERα expressions were up-regulated in SKOV-3 cells compared with normal ovarian IOSE80 epithelial cells. Conversely, down-regulation of ERβ was observed in SKOV-3 cells. Forced over-expression of ERα and ERβ in SKOV-3 cells was manipulated to establish ERα+ and ERβ+ SKOV-3 cell lines. Incubation of ERα+ SKOV-3 cells with ERs agonist 17β-estradiol (E2) significantly enhanced sema 4D expression and rate of cell proliferation. Incubated with E2, ERβ+ SKOV-3 cells showed lower sema 4D expression and cell proliferation. Blocking ERα and ERβ activities with ICI182-780 inhibitor, sema 4D expressions and cell proliferation of ERα+ and ERβ+ SKOV-3 cells were recovered to control levels. Taken together, the data showed that sema 4D expression was positively correlated with the progress of ovarian cancer. ERα positively regulated sema 4D expression and accelerated cell proliferation. ERβ negatively regulated sema 4D expression and inhibited cell multiplication.

Humans , Female , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/metabolism , Ovarian Neoplasms/metabolism , Semaphorins/metabolism , Biomarkers, Tumor/metabolism , Cell Proliferation , Down-Regulation , Semaphorins/genetics
Yonsei Medical Journal ; : 59-66, 2017.
Article in English | WPRIM | ID: wpr-65062


PURPOSE: Loss of AT-rich DNA-interacting domain 1A (ARID1A) has been identified as a driving mutation of ovarian clear cell carcinoma (O-CCC), a triple-negative ovarian cancer that is intermediary between serous and endometrioid subtypes, in regards to molecular and clinical behaviors. However, about half of O-CCCs still express BAF250a, the protein encoded by ARID1A. Herein, we aimed to identify signatures of ARID1A-positive O-CCC in comparison with its ARID1A-negative counterpart. MATERIALS AND METHODS: Seventy cases of O-CCC were included in this study. Histologic grades and patterns of primary tumor, molecular marker immunohistochemistry profiles, and clinical outcomes were analyzed. RESULTS: Forty-eight (69%) O-CCCs did not express BAF250a, which were designated as "ARID1A-negative." The other 22 (31%) O-CCCs were designated as "ARID1A-positive." ARID1A-positive tumors were more likely to be histologically of high grades (41% vs. 10%, p=0.003), ERβ-positive (45% vs. 17%, p=0.011), and less likely to be HNF1β-positive (77% vs. 96%, p=0.016) and E-cadherin-positive (59% vs. 83%, p=0.028) than ARID1A-negative tumors. Patient age, parity, tumor stage were not significantly different in between the two groups. Cancer-specific survival was not significantly different either. CONCLUSION: We classified O-CCCs according to ARID1A expression status. ARID1A-positive O-CCCs exhibited distinct immunohistochemical features from ARID1A-negative tumors, suggesting a different underlying molecular event during carcinogenesis.

Adult , Aged , Female , Humans , Middle Aged , Adenocarcinoma, Clear Cell/metabolism , Biomarkers, Tumor/metabolism , Cadherins/metabolism , Estrogen Receptor beta/metabolism , Immunohistochemistry , Mutation , Neoplasm Proteins/metabolism , Nuclear Proteins/metabolism , Ovarian Neoplasms/metabolism , Transcription Factors/metabolism
Int. j. morphol ; 33(1): 388-392, Mar. 2015. ilus
Article in Spanish | LILACS | ID: lil-743815


Las hormonas esteroidales tienen un papel esencial en la fisiología reproductiva, actúan en el ovario estableciendo comunicación entre este y la glándula hipofisiaria y también en forma paracrina como reguladores locales. Se ha descrito expresión de receptores de estrógeno a nivel de ovarios fetales, neonatales y adulto, siendo necesario determinar cuales son los tipos celulares que expresan estos receptores. El ovario ovino es estereogénico activo desde la etapa fetal y por lo tanto los esteroides desempeñan un importante papel en el desarrollo gonadal. La regulación del crecimiento folicular está relacionado a varios factores por un lado la secreción de gonadotropinas por la hipófisis interviene durante el desarrollo folicular tardío, existiendo evidencias de una acción intra-ovárica directa de los estrógenos, en la regulación del crecimiento folicular temprano. Nuestro objetivo fue, evaluar la expresión y distribución de receptores de estrógeno b en las distintas poblaciones celulares del ovario de la oveja prepúber.

Steroid hormones play an essential role in reproductive physiology, acting in the ovary establishing communication between it and the pituitary gland as well as local paracrine regulators. Described estrogen receptor expression level fetal, neonatal and adult ovaries, which are necessary to determine the cell types that express these receptors. Sheep ovarian stereogenic is active from the fetal stage and therefore steroids play an important role in gonadal development. The regulation of follicle growth is related to several factors on the one hand the secretion of gonadotropins by the pituitary follicular development occurring during late, there was evidence of a direct intra-ovarian estrogen action in the early follicular growth regulation. Our objective was to evaluate the expression and distribution of estrogen receptor b in different cell populations of the ovary of prepubertal sheep.

Animals , Ovary/metabolism , Sexual Maturation , Sheep , Estrogen Receptor beta/metabolism , Immunohistochemistry
The Korean Journal of Gastroenterology ; : 201-208, 2014.
Article in Korean | WPRIM | ID: wpr-192823


Gender difference in the incidence of colorectal cancer is well known and has been supported by various epidemiologic studies. In Korea, women have lower incidence of colorectal cancer and adenoma, and the incidence in men has recently increased. Hormone replacement therapy in menopausal women is preventive of colorectal cancer but can cause cardiovascular diseases and breast cancer. Estrogen exerts diverse effects through estrogen receptors, ERalpha and ERbeta. ERbeta is associated with anti-proliferation and apoptosis. The ratio of ERalpha/ERbeta is important in the protection and tumorigenesis of colorectal cancer. Therefore ERbeta modulation has been investigated for preventing or treating colorectal cancer and avoiding adverse effects of estrogen at the same time. In addition, the gender-difference in the incidence of colorectal cancer should be taken into account when making guidelines on colorectal surveillance for Korean population.

Humans , Adenoma/diagnosis , Colorectal Neoplasms/diagnosis , Estradiol Dehydrogenases/metabolism , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/metabolism , Estrogens/metabolism , Sex Factors
Int. j. morphol ; 28(2): 483-487, June 2010. ilus
Article in English | LILACS | ID: lil-577141


The present study was planned to demonstrate the detailed immunoreactive (IR) distribution pattern of estrogen receptors (ER) in hippocampus of 15 female rats, adult, female Wistar rats in estrous phase. 30 µm thick setions of hippocampal region fixed (4 percent buffered paraformaldehyde) were obtained with cryostat. The sections were processed free- floating for immunolocalization of ER using, mouse monoclonal anti-ER-a antibody with PAP technique. The results showed presence of ER immunoreactive neurons in all the subfields of hippocampus with some variations. In cornua ammonis (CA) maximum ER positive (+ve) neurons were localized in CA3 region. Layer analysis showed maximum localization in the stratum oriens (SO) region. In other subfields and layers of CA the IR neurons were comparatively less in number. The morphological characters of all ER +ve neurons showed them to be interneurons both in CA as well as in Dentate gyrus (DG).

El estudio fue diseñado para demostrar el patrón de distribución inmunorreactivo (IR) detallado de los receptores estrogénicos (RE) en el hipocampo de 15 ratas Wistar, hembras, adultas, en fase de estro. Fueron obtenidas secciones 30 µm de grosor con un crióstato, de la región del hipocampo fijadas por perfusión (4 por ciento de paraformaldehído tamponado). Las secciones fueron procesadas, por libre flotación, para la inmunolocalización de RE utilizando anticuerpo monoclonal de ratón anti-ER-a con la técnica de PAP. Los resultados mostraron la presencia de neuronas inmunorreactivas ER en todos los subcampos del hipocampo con algunas variaciones. En el cuerno ventral (CA) la mayor zona RE positiva (+ ve) de las neuronas se localizaron en la región CA3. El análisis de las capas mostró la localización máxima en la región del estrato oriens (SO). En otros subcampos y capas de la CA las neuronas IR fueron comparativamente menores en número. Las características morfológicas de todas las neuronas RE + ve resultaron ser interneuronas tanto en el CA como en el giro dentado (DG).

Animals , Female , Rats , Hippocampus/anatomy & histology , Hippocampus/metabolism , Receptors, Estrogen/metabolism , Hippocampus/ultrastructure , Immunohistochemistry , Interneurons/metabolism , Rats, Wistar , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/metabolism
Braz. j. med. biol. res ; 43(2): 195-200, Feb. 2010. graf
Article in English | LILACS | ID: lil-538230


Variations in the estrogenic activity of the phytoestrogen-rich plant, Pueraria mirifica, were determined with yeast estrogen screen (YES) consisting of human estrogen receptors (hER) hERá and hERâ and human transcriptional intermediary factor 2 (hTIF2) or human steroid receptor coactivator 1 (hSRC1), respectively, together with the â-galactosidase expression cassette. Relative estrogenic potency was expressed by determining the â-galactosidase activity (EC50) of the tuber extracts in relation to 17â-estradiol. Twenty-four and 22 of the plant tuber ethanolic extracts interacted with hERá and hERâ, respectively, with a higher relative estrogenic potency with hERâ than with hERá. Antiestrogenic activity of the plant extracts was also determined by incubation of plant extracts with 17â-estradiol prior to YES assay. The plant extracts tested exhibited antiestrogenic activity. Both the estrogenic and the antiestrogenic activity of the tuber extracts were metabolically activated with the rat liver S9-fraction prior to the assay indicating the positive influence of liver enzymes. Correlation analysis between estrogenic potency and the five major isoflavonoid contents within the previously HPLC-analyzed tuberous samples namely puerarin, daidzin, genistin, daidzein, and genistein revealed a negative result.

Animals , Rats , Estrogen Receptor alpha/analysis , Estrogen Receptor beta/analysis , Liver/drug effects , Plant Extracts/pharmacology , Pueraria/chemistry , Biological Assay , Chromatography, High Pressure Liquid , Estradiol/metabolism , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/metabolism , Isoflavones/analysis , Isoflavones/metabolism , Liver/metabolism , Nuclear Receptor Coactivator 1/metabolism , /metabolism , beta-Galactosidase/analysis , beta-Galactosidase/antagonists & inhibitors