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1.
Zhonghua Fu Chan Ke Za Zhi ; 54(7): 464-469, 2019 Jul 25.
Artigo em Chinês | MEDLINE | ID: mdl-31365959

RESUMO

Objective: To evaluate the effects of parthenolide on estradiol-synthesizing enzyme, steroidogenic acute regulatory protein (StAR), and ER isoforms,VEGF in human endometriotic stromal cells. Methods: Primary endometriotic stromal cells were treated with different concentrations (1, 5, 10 and 20 µmol/L) of parthenolide. The mRNA of StAR, ER isoforms (ERα and ERß), PR, vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), tumour necrosis factor-α (TNFα), tumour necrosis factor receptor (TNFR) 1, TNFR2 were measured by real-time PCR. The levels of estradiol and progesterone in the cell supernatant were measured by ELISA. Results: Different concentrations of parthenolide could up-regulate the mRNA of StAR in primary endometriotic stromal cells (F=5.722, P<0.05); the mRNA of StAR in the group of 20 µmol/L was significantly higher than that of the control group [2.6±0.3 versus 1.0, P<0.01]. Different concentrations of parthenolide could down-regulate the mRNA of ERα (F=6.921, P<0.01); the mRNA of ERα in the group of 20 µmol/L and 10 µmol/L were significantly lower than those of the control group [0.2±0.3 versus 0.3±0.3 versus 1.0, all P<0.05]. Different concentrations of parthenolide could down-regulate the ratios of ERα/ERß mRNA levels (F=4.209, P<0.05). Different concentrations of parthenolide could up-regulate the mRNA of VEGF and TNFR1 (F=10.964, P<0.01; F=7.286, P<0.01). There were no statiscal significances with different concentrations of parthenolide on the mRNA of ERß, PR, IL-6, TNFα and TNFR2, and the levels of estradiol and progesterone in the cell supernatant (all P>0.05). Conclusions: Parthenolide may regulate the expression of estradiol-synthesizing enzyme, ER isoforms and angiogenesis in endometriotic stromal cells. Parthenolide may promote the development of endometriosis.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Endometriose , Endométrio/efeitos dos fármacos , Sesquiterpenos/farmacologia , Células Estromais/metabolismo , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Endometriose/induzido quimicamente , Endometriose/genética , Endométrio/metabolismo , Endométrio/patologia , Estradiol , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Isoformas de Proteínas , Células Estromais/efeitos dos fármacos , Células Estromais/patologia , Fator de Necrose Tumoral alfa/metabolismo
2.
Anticancer Res ; 39(8): 4149-4164, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366500

RESUMO

BACKGROUND/AIM: Signaling regulation of myeloid zinc finger 1 (MZF1) has been implicated in the progression of many human malignancies; however, the mechanistic action of MZF1 in triple-negative breast cancer (TNBC) progression remains elusive. In this study, the aim was to investigate the molecular mechanisms of MZF1 and its functional role in TNBC cellular migration and invasion. MATERIALS AND METHODS: Hs578T and MDA-MB-231 cells were transfected to stably express the acidic domain of MZF1 (MZF160-72), or were transfected with MZF1-specific or ELK1-specific short hairpin RNA (shRNA). Changes in cell morphology and distributions of cellular proteins were observed and subsequently migration and invasion were measured by wound healing and transwell assays. Expression levels of epithelial-mesenchymal transition (EMT)-related genes were carried out using immunoblotting and quantitative reverse transcription-polymerase chain reaction (RT-PCR) assays. Data of transcriptional regulation were obtained from promoter-luciferase reporter and chromatin immunoprecipitation (ChIP) assays. RESULTS: Herein, we found that MZF1 in high-level MZF1-expressing TNBC cells is associated with cell migration, invasion, and mesenchymal phenotype. MZF1 interacted with the promoter region of insulin-like growth factor 1 receptor (IGF1R) to drive invasion and metastasis of high-level MZF1-expressing TNBC cells. Exogenous expression of the acidic domain of MZF1 repressed the binding of endogenous MZF1 to IGF1R promoter via blocking the interaction with ETS-like gene 1 (ELK1). This blockage not only caused MZF1 protein degradation, but also restrained ELK1 nuclear localization in high-level MZF1-expressing TNBC cells. MZF1, but not ELK1, was necessary for the retention of mesenchymal phenotype by repressing IGF1R promoter activity in TNBC cells expressing high levels of MZF1. Activation of the IGF1R-driven p38MAPK-ERα-slug-E-cadherin signaling axis mediated the conversion of mesenchymal cell to epithelial phenotype, caused by MZF1 destabilization. These results suggest that MZF1 is an oncogenic inducer. CONCLUSION: Blocking of the MZF1/ELK1 interaction to reduce MZF1 protein stability by saturating the endogenous MZF1/ELK1 binding domains might be a promising therapeutic strategy for the treatment of high-level MZF1-expressing TNBC.


Assuntos
Fatores de Transcrição Kruppel-Like/genética , Receptores de Somatomedina/genética , Neoplasias de Mama Triplo Negativas/genética , Proteínas Elk-1 do Domínio ets/genética , Caderinas/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proteínas de Ligação a DNA/genética , Transição Epitelial-Mesenquimal/genética , Receptor alfa de Estrogênio/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Regiões Promotoras Genéticas/genética , Domínios Proteicos/genética , Transdução de Sinais/genética , Neoplasias de Mama Triplo Negativas/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética
3.
Mol Biol (Mosk) ; 53(3): 502-512, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31184616

RESUMO

BRCA1 (breast cancer 1) protein is involved in the genome stability maintenance participating in homologous recombination-dependent DNA repair. Disruption of BRCA1 functioning is associated with breast and ovarian cancer. Despite the important role of BRCA1 in DNA repair in all cell types, the development of BRCA1-associated cancer takes place mainly in estrogen-dependent tissues such as breast and ovarian ones. Using breast cancer cell line MCF-7 it was demonstrated in in vitro experiments that the estrogen 17ß-estradiol (E2), phytoestrogens (genistein and apigenin) and antiestrogens (tamoxifen and fulvestrant) inhibited estrogen receptor (ERα) expression while only genistein influenced BRCA1 increasing its expression. In hypoxia, that is an important factor of solid tumors progression, the decrease of BRCA1 and ERα expression was demonstrated in MCF-7 cells. Therefore, hypoxia influences both BRCA1-dependent DNA repair and hormonal regulation of breast cancer cell growth. Taken together, obtained results demonstrate a relationship between BRCA1 and steroid hormones signal transduction pathways in breast cancer cells and point out to the importance of complex BRCA1 and ERa expression regulation mechanisms studies including epigenetic gene expression regulation.


Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/genética , Regulação Neoplásica da Expressão Gênica , Epigênese Genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7
4.
Int J Mol Sci ; 20(11)2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31146345

RESUMO

Breast cancer remains the major cause of cancer-induced morbidity and mortality in women. Among the different molecular subtypes, luminal tumors yet considered of good prognosis often develop acquired resistance to endocrine therapy. Recently, misregulation of ERα36 was reported to play a crucial role in this process. High expression of this ERα isoform was associated to preneoplastic phenotype in mammary epithelial cells, disease progression, and enhanced resistance to therapeutic agents in breast tumors. In this study, we identified two mechanisms that could together contribute to ERα36 expression regulation. We first focused on hsa-miR-136-5p, an ERα36 3'UTR-targeting microRNA, the expression of which inversely correlated to the ERα36 one in breast cancer cells. Transfection of hsa-miR136-5p mimic in MCF-7 cells resulted in downregulation of ERα36. Moreover, the demethylating agent decitabine was able to stimulate hsa-miR-136-5p endogenous expression, thus indirectly decreasing ERα36 expression and counteracting tamoxifen-dependent stimulation. The methylation status of ERα36 promoter also directly modulated its expression level, as demonstrated after decitabine treatment of breast cancer cell and confirmed in a set of tumor samples. Taken together, these results open the way to a direct and an indirect ERα36 epigenetic modulation by decitabine as a promising clinical strategy to counteract acquired resistance to treatment and prevent relapse.


Assuntos
Neoplasias da Mama/genética , Epigênese Genética , Receptor alfa de Estrogênio/genética , Regiões 3' não Traduzidas , Adulto , Idoso , Neoplasias da Mama/patologia , Metilação de DNA , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Receptor alfa de Estrogênio/química , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Células MCF-7 , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade
5.
Gene ; 710: 202-209, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31163192

RESUMO

Estrogen regulates bone homeostasis and has a cardio-protective effect. Its physiological functions are mediated through receptors (ER) whose expression can be regulated by presence or absence of polymorphisms. However, the association between ER polymorphisms and BMD as well as lipids are inconsistent. The aim of the study was to investigate whether polymorphisms in ESR are associated with bone mineral density (BMD) and lipids in a cohort of Indian women. We studied PvuII, XbaI polymorphisms in ESR1 and AluI, RsaI polymorphisms in ESR2 genes and their association with bone mineral density (BMD) and lipids in premenopausal (n = 293, mean age: 33.01 ±â€¯5.23 years) and postmenopausal (n = 145, mean age: 56.91 ±â€¯7.1 years) women from Northeast India. AluI and RsaI polymorphisms in ESR2 gene were associated with BMD in postmenopausal women. Logistic regression analysis adjusted for age, BMI, tobacco and alcohol consumption revealed that xx genotype in XbaI polymorphism is associated with osteopenia at spine (OR = 3.3, 95% CI = 1.067-10.204) in postmenopausal women suggesting that allele X is protective (OR = 0.419, 95% CI = 0.177-0.991). Genotype aa in AluI polymorphism, seemed to be protective (OR = 0.092 for osteopenia; OR = 0.152 for osteoporosis) at spine whereas A allele was associated with osteopenia at femur (OR = 2.123, 95% CI = 1.079-4.166) in postmenopausal women. Allele r of RsaI polymorphism, was associated with osteoporosis at spine (OR = 3.222, 95% CI = 1.302-7.96). Thus, AIuI polymorphism of ESR2 gene was associated with spinal and femoral BMD whereas RsaI only with spinal BMD in postmenopausal women and ESR genotypes were not associated with lipids.


Assuntos
Doenças Ósseas Metabólicas/genética , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Lipídeos/análise , Polimorfismo de Nucleotídeo Único , Pós-Menopausa/genética , Pré-Menopausa/genética , Absorciometria de Fóton , Adulto , Densidade Óssea , Doenças Ósseas Metabólicas/metabolismo , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Fêmur/diagnóstico por imagem , Estudos de Associação Genética , Humanos , Índia , Modelos Logísticos , Pessoa de Meia-Idade , Coluna Vertebral/diagnóstico por imagem
6.
Ecotoxicol Environ Saf ; 181: 463-471, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31228822

RESUMO

To assess the effect of exposure to persistent organic pollutants (POPs) on the estrogen receptor (ER) signaling pathway in Baikal seals (Pusa sibirica), we investigated the molecular characterizations and functions of two Baikal seal ER (bsER) isoforms, bsERα and bsERß. The bsERα and bsERß cDNA clones isolated have an open reading frame of 595 and 530 amino acid residues, respectively. The tissue distribution analyses of bsER mRNAs showed that bsERα transcripts were primarily found in the ovary and uterus, and bsERß in the muscle in wild Baikal seals. The immunofluorescence staining assay showed that 17ß-estradiol (E2) treatment promoted the nuclear translocation of in vitro-expressed bsERα. Transient transfection of bsERα in U2OS cells enhanced the transcription of pS2, an ER target gene of E2. We then measured bsER-mediated transactivation potencies of POPs in an in vitro reporter gene assay system, in which a bsERα or bsERß expression vector was transfected into COS-1 cells. For comparison, transactivation potencies of POPs on mouse ERs (mERα and mERß) were also evaluated in the same manner. Results showed significant dose-dependent responses of bsERs and mERs when treated with p,p'-dichlorodiphenyltrichloroethane (p,p'-DDT), and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE). bsERs and mERs showed no response when exposed to polychlorinated biphenyls (PCBs) or 2,3,7,8-tetrachlorodibenzo-p-dioxin. Comparison of the dose-response curves of DDTs across species (bsERs vs. mERs) showed that bsERα had a response similar to mERα, but bsERß was less sensitive than mERß. Comparing the lowest observable effective concentrations of p,p'-DDT (2.8 µM) and p,p'-DDE (10 µM) for in vitro bsERα-mediated transactivation with their hepatic concentrations in wild Baikal seals indicated that some individuals accumulated these compounds at levels comparable to the effective concentrations, suggesting the potential disruption of the bsERα signaling pathway in the wild population by these compounds. Co-transfection experiments with bsER and the aryl hydrocarbon receptor (AHR) suggested that high accumulation of estrogenic compounds exerts a synergistic effect with dioxin-like congeners on ER signaling through AHR activation in the wild seal population.


Assuntos
Dioxinas e Compostos Semelhantes a Dioxinas/toxicidade , Poluentes Ambientais/toxicidade , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Ativação Transcricional/efeitos dos fármacos , Animais , Dioxinas e Compostos Semelhantes a Dioxinas/metabolismo , Poluentes Ambientais/metabolismo , Feminino , Camundongos , RNA Mensageiro/metabolismo , Focas Verdadeiras
7.
Biomed Res Int ; 2019: 2304128, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31058185

RESUMO

Breast cancer is the most common cancer among women and is considered a major public health concern worldwide. Biogeography-based optimization (BBO) is a novel metaheuristic algorithm. This study analyzed the relationship between the clinicopathologic variables of breast cancer using Cox proportional hazard (PH) regression on the basis of the BBO algorithm. The dataset is prospectively maintained by the Division of Breast Surgery at Kaohsiung Medical University Hospital. A total of 1896 patients with breast cancer were included and tracked from 2005 to 2017. Fifteen general breast cancer clinicopathologic variables were collected. We used the BBO algorithm to select the clinicopathologic variables that could potentially contribute to predicting breast cancer prognosis. Subsequently, Cox PH regression analysis was used to demonstrate the association between overall survival and the selected clinicopathologic variables. C-statistics were used to test predictive accuracy and the concordance of various survival models. The BBO-selected clinicopathologic variables model obtained the highest C-statistic value (80%) for predicting the overall survival of patients with breast cancer. The selected clinicopathologic variables included tumor size (hazard ratio [HR] 2.372, p = 0.006), lymph node metastasis (HR 1.301, p = 0.038), lymphovascular invasion (HR 1.606, p = 0.096), perineural invasion (HR 1.546, p = 0.168), dermal invasion (HR 1.548, p = 0.028), total mastectomy (HR 1.633, p = 0.092), without hormone therapy (HR 2.178, p = 0.003), and without chemotherapy (HR 1.234, p = 0.491). This number was the minimum number of discriminators required for optimal discrimination in the breast cancer overall survival model with acceptable prediction ability. Therefore, on the basis of the clinicopathologic variables, the survival prediction model in this study could contribute to breast cancer follow-up and management.


Assuntos
Neoplasias da Mama/epidemiologia , Gerenciamento Clínico , Filogeografia/métodos , Prognóstico , Algoritmos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Intervalo Livre de Doença , Receptor alfa de Estrogênio/genética , Feminino , Terapia de Reposição Hormonal , Humanos , Metástase Linfática , Mastectomia , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Receptor ErbB-2/genética , Receptores de Progesterona/genética
8.
Environ Pollut ; 251: 30-36, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31071630

RESUMO

The wide use of chiral fungicides has generated interest in the stereoselectivity of their ecotoxicological effects. However, there are few studies about the potential endocrine-disrupting effects (EDEs) of chiral fungicides. This study evaluated the hormone receptor activities of the chiral triazole fungicide prothioconazole and its metabolite using reporter gene assays. The results indicated that prothioconazole and its metabolite possessed EDEs, and the metabolite exerted more activities than the activities of the parent compound, suggesting that the metabolic process is toxification. Stereoselective EDEs were observed, and the S-enantiomers possessed greater hormonal effects than those possessed by the R-enantiomers; the REC20 values ranged from 7.9 × 10-10 to 6.4 × 10-7 M for the thyroid hormone effects and from 3.2 × 10-9 to 7.8 × 10-8 M for the estrogenic effects. The molecular docking results revealed that the stereoselective EDEs of prothioconazole and its metabolite were partially attributed to enantiospecific receptor binding affinities. Overall, our results reveal that prothioconazole and its metabolite might disrupt the balance of the endocrine system by affecting the function of multiple nuclear hormone receptors and that they have the potential to affect the developmental and reproductive systems in humans.


Assuntos
Disruptores Endócrinos/metabolismo , Disruptores Endócrinos/toxicidade , Fungicidas Industriais/metabolismo , Fungicidas Industriais/toxicidade , Triazóis/metabolismo , Triazóis/toxicidade , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Cercopithecus aethiops , Disruptores Endócrinos/química , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Fungicidas Industriais/química , Genes Reporter , Humanos , Simulação de Acoplamento Molecular , Estereoisomerismo , Receptores beta dos Hormônios Tireóideos/genética , Receptores beta dos Hormônios Tireóideos/metabolismo , Triazóis/química
9.
Mol Med Rep ; 19(6): 5087-5096, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059046

RESUMO

The present study aimed to investigate the inhibitory effects and the mechanisms underlying 17ß­estradiol (E2) effects on triglyceride synthesis and insulin resistance in skeletal muscle tissues and cells. Ovariectomy (OVX) was performed on 6­month­old female rats treated with or without E2. Subsequently, various serum biochemical markers were measured. Additionally, pathological alterations of the uterus, liver and skeletal muscle were analyzed, and the content of triglycerides (TG) in muscle was detected. Differentiated myotubes formed by C2C12 cells were treated with palmitic acid (PA) or pretreated with E2, estrogen receptor (ESR) 1 agonist propylpyrazoletriol (PPT) and ESR2 agonist diarylpropionitrile (DPN). Subsequently, the mRNA or protein expression levels of ESR1/2, peroxisome proliferator activated receptor α (PPARα), CD36 molecule (CD36), fatty acid synthase (FASN), perilipin 2 (PLIN2), phosphorylated acetyl­CoA carboxylase α (p­ACACA), p­AKT serine/threonine kinase (p­AKT) and p­mitogen­activated protein kinase 8 (p­MAPK8) were analyzed in skeletal muscle or in C2C12 cells by reverse transcription­semi­quantitative polymerase chain reaction and western blotting. The present results suggested that treatment with E2 inhibited OVX­induced body weight gain, TG accumulation and insulin resistance. The protein or mRNA expression levels of ESR1, CD36, PPARα, p­ACACA and p­AKT were decreased, whereas the protein or mRNA expression levels of ESR2, PLIN2, FASN and p­MAPK8 were increased in the OVX group. Of note, treatment with E2 restored the expression levels of the aforementioned factors. In C2C12 cells, treatment with E2 or PPT reversed the alterations induced by treatment with PA. In contrast, pretreatment with DPN did not influence the effect of PA. Collectively, E2 was able to interact with ESR1, thus activating the CD36­PPARα pathway, decreasing the level of TG in the muscles and improving insulin resistance in skeletal muscles and C2C12 cells.


Assuntos
Estradiol/farmacologia , Receptor alfa de Estrogênio/metabolismo , Triglicerídeos/biossíntese , Animais , Linhagem Celular , Regulação para Baixo/efeitos dos fármacos , Receptor alfa de Estrogênio/agonistas , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Feminino , Resistência à Insulina , Camundongos , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Ovariectomia , Ácido Palmítico/farmacologia , Perilipina-2/genética , Perilipina-2/metabolismo , Fenóis/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirazóis/farmacologia , Ratos , Ratos Sprague-Dawley , Regulação para Cima/efeitos dos fármacos
10.
Mol Cell Biochem ; 458(1-2): 207-217, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31077012

RESUMO

Leptin induces ovarian cancer cell invasion via overexpression of MMP7, MMP9, and upA. In addition, the key role of ERα in leptin-increased cell growth was indicated. However, the influence of ER on leptin-mediated cell invasion remains still unknown. The present study was designed to evaluate the E2-independent effect of ERα/ß on leptin-mediated cell invasion and cell proliferation in ovarian cancer. We utilized SKOV3 cancer (expressing OB-Rb and ERα/ß, insensitive to estrogen) and OVCAR3 (expressing OB-Rb) cell lines to show the involvement of ER in leptin-mediated effects in an E2-independent manner. MTT, BrdU, and BD matrigel invasion assays were applied to analyze cell growth, proliferation, and invasion. The siRNA approach was used to confirm the role of ERα/ß in leptin effects. Moreover, western blotting and Real-time PCR were employed to detect the OB-Rb, ER, MMP9/7, and upA proteins and mRNAs. Leptin, in the absence of E2, increased ERα expression in SKOV3 cells, which was attenuated using knockdown of OB-Rb gene by siRNA. The effect of leptin on the cell growth was promoted in the presence of PPT, but not in the presence of DNP and E2, which was lost when OB-Rb siRNA was transfected. Furthermore, ERα gene silencing and/or pre-incubation with ER antagonist (ICI 182,780, 10 nM) significantly reduced cell invasion and MMP9 expression stimulated by leptin. In conclusion, our findings demonstrated that ERα, but not ERß, is involved in leptin-induced ovarian cancer in an E2-independent manner, providing new evidence for cancer progression in obesity-associated ovarian cancer.


Assuntos
Carcinoma Epitelial do Ovário/metabolismo , Receptor alfa de Estrogênio/metabolismo , Leptina/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Ovarianas/metabolismo , Receptores para Leptina/metabolismo , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Receptor alfa de Estrogênio/genética , Feminino , Humanos , Leptina/genética , Proteínas de Neoplasias/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Receptores para Leptina/genética
11.
Anticancer Res ; 39(5): 2647-2659, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31092464

RESUMO

BACKGROUND/AIM: The aim of the present study was to analyze metastasized breast cancer (BC) patients with regard to the discordance of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). We especially aimed to analyze the association between the change of tumor biology and previous treatment or metastatic sites. PATIENTS AND METHODS: Patients with metastasized BC who were treated at the Department of Gynecology/Breast Center of the University Hospital of Cologne were analyzed. RESULTS: Loss of HER2 occurred more frequently in lymph node metastases that were not in the axillary region (p=0.026). Letrozole showed a significant correlation with loss of ER and/or PR (p=0.041). Improved overall survival and post-metastasis survival were noticed with a gain of HER2 (p=0.044 and p=0.009, respectively) and concordant positive ER and PR status (p=0.002 and p=0.001, respectively). CONCLUSION: The discordance of receptors and the dependence of BC on therapies as well as metastatic sites stresses the necessity of early sample taking to offer patients suitable therapy options.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Recidiva Local de Neoplasia/genética , Segunda Neoplasia Primária/genética , Adulto , Idoso , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Linfonodos/metabolismo , Linfonodos/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Segunda Neoplasia Primária/tratamento farmacológico , Segunda Neoplasia Primária/patologia , Receptor ErbB-2/genética , Receptores de Progesterona/genética
12.
Int J Mol Sci ; 20(8)2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995757

RESUMO

The amplification of estrogen receptor alpha (ERα) encoded by the ESR1 gene has been described as having a prognostic role in breast cancer patients. However, increased dosage of the ESR1 gene (tested by real-time PCR) is also observed in ER-negative breast cancers, which might suggest the expression of alternative isoforms of ERα (other than classical ERα of 66 kDa). In the current work, we have investigated the ESR1 gene dosage in 402 primary breast cancer patients as well as the expression of ERα isoforms-ERα66 and ERα36-on mRNA and protein levels. The obtained results were correlated with clinicopathological data of the patients. Results showed that increased ESR1 gene dosage is not related to ESR1 gene amplification measured by fluorescent in situ hybridization (FISH), but it correlates with the decreased expression of ERα66 isoform (p = 0.01). Interestingly, the short ER isoform ERα36 was expressed in samples with increased ESR1 gene dosage, suggesting that genomic aberration might influence the expression of that particular isoform. Similarly to ESR1 increased gene dosage, high ERα36 expression was linked with the decreased disease-free survival of the patients (p = 0.05), which was independent of the status of the classical ERα66 level in breast tumors.


Assuntos
Neoplasias da Mama/genética , Receptor alfa de Estrogênio/genética , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Mama/patologia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Prognóstico , Isoformas de Proteínas/genética , Regulação para Cima
13.
Oncol Rep ; 41(6): 3517-3526, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31002359

RESUMO

Resveratrol, a plant­derived stilbene compound, has exhibited anticancerous properties, including breast cancer. Stilbenes have a molecular structure highly similar to estrogen and have the ability to bind estrogen receptors and regulate activity. Numerous studies have demonstrated the effectiveness of resveratrol in estrogen receptor­positive (ER­positive) subtypes of breast cancer, yet the effects in ER­negative subtypes, including triple­negative breast cancer (TNBC), have been limited. In the present study, resveratrol and 28 analogues were tested on a panel of ER­positive and TNBC cell lines to determine effects on cell viability. Several compounds exhibited significant impacts on cell viability and suggested changes in cell morphology, with high potency of select compounds compared to resveratrol observed in a dose­dependent manner. Due to the lack of estrogen receptors in TNBC and the estrogenic nature of stilbenes, regulation of breast cancer­associated cellular pathways was assessed for five analogues shown to significantly inhibit cell viability. Top regulated pathways included apoptosis (confirmed by caspase assay) and DNA damage repair. Overall, our results indicated several resveratrol analogues to be active in ER­negative phenotypes, acting through an ER receptor­independent manner, supporting further investigation into their mechanism of action and use as potential chemotherapeutics in higher­risk breast cancer cases.


Assuntos
Proliferação de Células/efeitos dos fármacos , Receptor alfa de Estrogênio/genética , Resveratrol/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Feminino , Humanos , Transdução de Sinais/efeitos dos fármacos , Estilbenos/farmacologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
14.
Gynecol Oncol ; 154(1): 199-206, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30987772

RESUMO

OBJECTIVE: Endocrine therapy is often considered as a treatment for hormone-responsive gynecologic malignancies. In breast cancer, activating mutations in the estrogen receptor (mutESR1) contribute to therapeutic resistance to endocrine therapy, especially aromatase inhibitors (AIs). The purpose of this study was to evaluate the frequency and clinical relevance of ESR1 genomic alterations in gynecologic malignancies. METHODS: DNA from FFPE tumor tissue obtained during routine clinical care for 9645 gynecologic malignancies (ovary, fallopian tube, uterus, cervix, vagina, vulvar, and placenta) was analyzed for all classes of genomic alterations (base substitutions (muts), insertions, deletions, rearrangements, and amplifications) in ESR1 by hybrid capture next generation sequencing. A subset of alterations was characterized in laboratory-based transcription assays for response to endocrine therapies. RESULTS: A total of 295 ESR1 genomic alterations were identified in 285 (3.0%) cases. mutESR1 were present in 86 (0.9%) cases and were more common in uterine compared to other cancers (2.0% vs <1%, respectively p < 0.001). mutESR1 were enriched in carcinomas with endometrioid versus serous histology (4.4% vs 0.2% respectively, p < 0.0001 in uterine and 3.5% vs 0.3% respectively, p = 0.0004 in ovarian carcinomas). In three of four patients with serial sampling, mutESR1 emerged under the selective pressure of AI therapy. Despite decreased potency of estrogen receptor (ER) antagonists in transcriptional assays, clinical benefit was observed following treatment with selective ER-targeted therapy, in one case lasting >48 months. CONCLUSIONS: While the prevalence of ESR1 mutations in gynecologic malignancies is low, there are significant clinical implications useful in guiding therapeutic approaches for these cancers.


Assuntos
Inibidores da Aromatase/administração & dosagem , Receptor alfa de Estrogênio/genética , Neoplasias dos Genitais Femininos/tratamento farmacológico , Neoplasias dos Genitais Femininos/genética , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Adulto , Inibidores da Aromatase/farmacologia , DNA de Neoplasias/genética , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Mutação , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Transcrição Genética/efeitos dos fármacos , Transcriptoma , Resultado do Tratamento , Adulto Jovem
15.
Breast Cancer Res Treat ; 175(3): 567-578, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30937657

RESUMO

PURPOSE: In early stage, ERα-positive breast cancer, concurrent use of endocrine therapy and chemotherapy has not been shown to be superior to sequential use. We hypothesized that genetic biomarkers can aid in selecting patients who would benefit from chemo-endocrine therapy. Our previous studies revealed that ZNF423 is a transcription factor for BRCA1 and an intronic single nucleotide polymorphism (SNP) in ZNF423, rs9940645, determines tamoxifen response. Here, we identified mitosis-related genes that are regulated by ZNF423 which led us to investigate taxane response in a rs9940645 SNP- and tamoxifen-dependent fashion. METHODS: The Cancer Genome Atlas (TCGA) breast cancer dataset was used to identify genes correlated with ZNF423. Quantitative reverse transcription PCR, chromatin immunoprecipitation, and luciferase reporter assays were used to validate the gene regulation. We used CRISPR/Cas9 to engineer paired ZR-75-1 cells which differ only in ZNF423 rs9940645 SNP genotype to test SNP-dependent phenotypes including cell cycle and cell viability. We validated our findings in an additional two breast cancer cell lines, Hs578T-ERα and HCC1500. RESULTS: Mitosis-related genes VRK1 and PBK, which encode histone H3 kinases, were experimentally validated to be regulated by ZNF423. ZNF423 knockdown decreased VRK1 and PBK expression and activity. Additionally, ZNF423 knockdown enhanced docetaxel-induced G2/M arrest and cytotoxicity through VRK1 or PBK regulation. Lastly, cells carrying the rs9940645 variant genotype had increased G2/M arrest and decreased cell viability when treated with docetaxel in combination with estradiol and 4-OH-TAM. CONCLUSIONS: We identified ZNF423 regulated genes involved in the G2/M phase of the cell cycle. 4-OH-TAM sensitized ERα-positive breast cancer cells to docetaxel in a ZNF423 SNP-dependent manner. Our findings suggest that patients with rs9940645 variant genotype may benefit from concurrent tamoxifen and docetaxel. This would impact a substantial proportion of patients because this SNP has a minor allele frequency of 0.47.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/genética , Docetaxel/farmacologia , Estradiol/farmacologia , Receptor alfa de Estrogênio/genética , Proteínas/genética , Tamoxifeno/análogos & derivados , Neoplasias da Mama/tratamento farmacológico , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Receptor alfa de Estrogênio/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Polimorfismo de Nucleotídeo Único , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas/metabolismo , Tamoxifeno/farmacologia
16.
Nat Commun ; 10(1): 1522, 2019 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-30944316

RESUMO

Recent studies have demonstrated that chromatin architecture is linked to the progression of cancers. However, the roles of 3D structure and its dynamics in hormone-dependent breast cancer and endocrine resistance are largely unknown. Here we report the dynamics of 3D chromatin structure across a time course of estradiol (E2) stimulation in human estrogen receptor α (ERα)-positive breast cancer cells. We identified subsets of temporally highly dynamic compartments predominantly associated with active open chromatin and found that these highly dynamic compartments showed higher alteration in tamoxifen-resistant breast cancer cells. Remarkably, these compartments are characterized by active chromatin states, and enhanced ERα binding but decreased transcription factor CCCTC-binding factor (CTCF) binding. We finally identified a set of ERα-bound promoter-enhancer looping genes enclosed within altered domains that are enriched with cancer invasion, aggressiveness or metabolism signaling pathways. This large-scale analysis expands our understanding of high-order temporal chromatin reorganization underlying hormone-dependent breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Cromatina/metabolismo , Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Núcleo Celular/metabolismo , Cromatina/química , Resistencia a Medicamentos Antineoplásicos , Epigênese Genética , Estradiol/farmacologia , Receptor alfa de Estrogênio/biossíntese , Receptor alfa de Estrogênio/genética , Feminino , Humanos , Células MCF-7 , Modelos Moleculares , Regiões Promotoras Genéticas , Ligação Proteica , Transdução de Sinais , Tamoxifeno/farmacologia , Fatores de Transcrição
17.
Toxicol Lett ; 310: 14-22, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30980910

RESUMO

Mechanism of PAH mixtures, using granulosa tumour cells, was investigated. Cells were exposed to a mixture of all 16 priority PAHs (M1) or a mixture of five PAHs not classified as human carcinogens (M2). The effect of siAHR, siAHRR and siNFKB2 on the expression of CYP1A1, CYP1B1, GSTM1, ERα, AR and cell proliferation was described. M1 decreased AhR and CYP1A1, while increased AhRR and ARNT expression. M2 also decreased AhR and CYP1A1 but had no effect on AhRR expression. siAHRR reversed the inhibitory effect of M1 on AhR and CYP1A1,while inhibitory effect of M2 was still observed. siNFKB2 reversed inhibitory effect of both mixtures on AhR and CYP1A1 expression and stimulatory effect of M1 on AhRR expression. siAHR reversed stimulatory effect of both mixtures on ERα expression. Stimulatory effect of M1 on cell proliferation was not observed in siAHR, was still observed in siESR1 cells. M2 had no effect on cell proliferation, however stimulatory effect was appeared in siAHR and siESR1cells. In conclusion: M1 by activation of AhRR and NFkB p52, but M2 only by activation of NFκB attenuated AhR signalling and ligand-induced CYP1A1 expression. Interaction between AhR and ER following M1 and M2 exposure is primarily initiated through AhR.


Assuntos
Misturas Complexas/toxicidade , Tumor de Células da Granulosa , Células da Granulosa/efeitos dos fármacos , Neoplasias Ovarianas , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Metabolismo Energético/efeitos dos fármacos , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Tumor de Células da Granulosa/genética , Tumor de Células da Granulosa/metabolismo , Tumor de Células da Granulosa/patologia , Células da Granulosa/metabolismo , Células da Granulosa/patologia , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Subunidade p52 de NF-kappa B/genética , Subunidade p52 de NF-kappa B/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo
18.
Cell Prolif ; 52(4): e12612, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31012189

RESUMO

OBJECTIVE: POU5F1 (OCT4) is implicated in cancer stem cell self-renewal. Currently, some studies have shown that OCT4 has a dual function in suppressing or promoting cancer progression. However, the precise molecular mechanism of OCT4 in breast cancer progression remains unclear. MATERIALS AND METHODS: RT-PCR and Western blot were utilized to investigate OCT4 expression in breast cancer tissues and cells. Cell proliferation assays and mouse models were applied to determine the effects of OCT4 on breast cancer cell proliferation. DNMT1 inhibitors, ChIP, CoIP, IHC and ERα inhibitors were used to explore the molecular mechanism of OCT4 in breast cancer. RESULTS: OCT4 was down-regulated in breast cancer tissues, and the overexpression of OCT4 promoted MDA-MB-231 cell proliferation and inhibited the proliferation of MCF-7 cells in vitro and in vivo, respectively. Two DNMT1 inhibitors (5-aza-dC and zebularine) suppressed OCT4-induced MDA-MB-231 cell proliferation through Ras/Raf1/ERK inactivation by targeting ISL1, which is the downstream of DNMT1. In contrast, OCT4 interacted with ERα, decreased DNMT1 expression and inactivated the Ras/Raf1/ERK signalling pathway in MCF-7 cells. Moreover, ERα inhibitor (AZD9496) reversed the suppression of OCT4-induced proliferation in MCF-7 cells via the activation of ERK signalling pathway. CONCLUSIONS: OCT4 is dependent on ERα to suppress the proliferation of breast cancer cells through DNMT1/ISL1/ERK axis.


Assuntos
Neoplasias da Mama/genética , Proliferação de Células/genética , DNA (Citosina-5-)-Metiltransferase 1/genética , Receptor alfa de Estrogênio/genética , Proteínas com Homeodomínio LIM/genética , Sistema de Sinalização das MAP Quinases/genética , Fator 3 de Transcrição de Octâmero/genética , Fatores de Transcrição/genética , Animais , Linhagem Celular Tumoral , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Células HEK293 , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transdução de Sinais/genética
19.
Mol Med Rep ; 19(5): 3989-4000, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30942443

RESUMO

Type 1 diabetes (T1D) is an autoimmune disease that is typically diagnosed in children. The aim of the present study was to identify potential genes involved in the pathogenesis of childhood T1D. Two datasets of mRNA expression in children with T1D were obtained from the Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) in children with T1D were identified. Functional analysis was performed and a protein­protein interaction (PPI) network was constructed, as was a transcription factor (TF)­target network. The expression of selected DEGs was further assessed using reverse transcription­quantitative polymerase chain reaction (RT­qPCR) analysis. Electronic validation and diagnostic value analysis of the identified DEGs [cytokine inducible SH2 containing protein (CISH), SR­related CTD associated factor 11 (SCAF11), estrogen receptor 1 (ESR1), Rho GTPase activating protein 25 (ARHGAP25), major histocompatibility complex, class II, DR ß4 (HLA­DRB4) and interleukin 23 subunit α (IL23A)] was performed in the GEO dataset. Compared with the normal control group, a total of 1,467 DEGs with P<0.05 were identified in children with T1D. CISH and SCAF11 were determined to be the most up­ and downregulated genes, respectively. Heterogeneous nuclear ribonucleoprotein D (HNRNPD; degree=33), protein kinase AMP­activated catalytic subunit α1 (PRKAA1; degree=11), integrin subunit α4 (ITGA4; degree=8) and ESR1 (degree=8) were identified in the PPI network as high­degree genes. ARHGAP25 (degree=12), HNRNPD (degree=10), HLA­DRB4 (degree=10) and IL23A (degree=9) were high­degree genes identified in the TF­target network. RT­qPCR revealed that the expression of HNRNPD, PRKAA1, ITGA4 and transporter 2, ATP binding cassette subfamily B member was consistent with the results of the integrated analysis. Furthermore, the results of the electronic validation were consistent with the bioinformatics analysis. SCAF11, CISH and ARHGAP25 were identified to possess value as potential diagnostic markers for children with T1D. In conclusion, identifying DEGs in children with T1D may contribute to our understanding of its pathogenesis, and such DEGs may be used as diagnostic biomarkers for children with T1D.


Assuntos
Diabetes Mellitus Tipo 1/diagnóstico , Transcriptoma , Área Sob a Curva , Estudos de Casos e Controles , Criança , Diabetes Mellitus Tipo 1/genética , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Redes Reguladoras de Genes , Humanos , Masculino , Mapas de Interação de Proteínas/genética , Curva ROC , Fatores de Processamento de Serina-Arginina/genética , Fatores de Processamento de Serina-Arginina/metabolismo , Proteínas Supressoras da Sinalização de Citocina/genética , Proteínas Supressoras da Sinalização de Citocina/metabolismo
20.
Cancer Treat Res Commun ; 19: 100123, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30826563

RESUMO

BACKGROUND: Breast cancer has, due its high incidence, the highest mortality of cancer in women. The most common molecular variety of breast cancer is luminal subtype that expresses estrogen and progesterone receptors. Estrogen receptor alpha (ERα), encoded by the estrogen receptor1 (ESR1) gene, is expressed in approximately 70% of all breast cancers, and hormonal therapy represents a major treatment modality in all stages of ER positive breast cancers. Acquired mutations in the ligand-binding domain (LBD) of ERα, referred as ESR1 mutation, result in resistance to different endocrine therapies leading to disease progression or recurrence. Recent studies reviled that these ESR1 mutations lead to constitutive activity of the estrogen receptor ER, meaning that the receptor is active in absence of its ligand conferring resistance against endocrine therapy and tumor growth. Published studies have not yet been able to determine the exact prevalence rate of ESR1 mutations, but set the outer boundaries between 11-55%. PURPOSE: The goal of the present study is to determine the frequency rate of ESR1 mutations in ER positive recurrent breast cancer by using digital droplet PCR (ddPCR) technique. MATERIALS AND METHODS: This retrospective study was conducted in the Multidisciplinary Breast Clinic of Antwerp University Hospital. The seven most common ESR1mutations (c.1138G>C (p. (E380Q)), c.1610A>G (p.(Y537C)), c.1613A>G (p.(p.D538G)), c.1607T>G (p.(L536R)), c.1387T>C (p.S463R)), c.16410A>C (p.(Y537S)), c.609T>A (p.(Y537N)) were assessed in available baseline plasma samples of 21 patients with ER positive recurrent breast cancer. Inclusion criteria for study participation were: female, age above 18 years, ER positive breast cancer, 5years adjuvant hormonal therapy of primary disease, and disease recurrence or metastasis during or after stop of endocrine therapy. ESR1 mutations were analyzed in cell-free DNA (cfDNA) by using digital droplet PCR (ddPCR). RESULTS: cfDNA was obtained from 21 patients with recurrent breast cancer. ESR1 mutations were found in 4/21 (19%; 95% CI, 5%-42%). The test sensitivity was lower than the targeted value <0.1% in 29% of patients (6/21). No significant statistical difference in baseline clinical characteristics was observed in patients with wild-type and mutant ER (p>0.05). Adjuvant endocrine therapy for primary disease was Tamoxifen (TAM) for 57% of patients (12 of 21) of whom 8 patients had received aromatase inhibitor (AI) after two years, while 43% of patients (9 of 21) had received AI as first line adjuvant hormonal therapy. All the patients had received aromatase inhibitor AI therapy in first or second line therapy with initially a variable period of good response. CONCLUSION: ESR1 mutation analysis could be determined in archived plasma samples using simple non-invasive methods. In the future, screening for mutation status could improve the therapeutic strategies in controlling ER signaling before the occurrence of wide spread disease metastasis.


Assuntos
Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Carcinoma Lobular/genética , Receptor alfa de Estrogênio/genética , Mutação , Recidiva Local de Neoplasia/genética , Adulto , Antineoplásicos Hormonais/uso terapêutico , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/secundário , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/secundário , Ácidos Nucleicos Livres/análise , Análise Mutacional de DNA , Receptor alfa de Estrogênio/sangue , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Prevalência , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
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