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PCSK9 promotes the lysosomal degradation of cell surface LDL receptor (LDLR). We analyzed how excess LDLR generated by PCSK9 deficiency is differently handled in male and female mice to possibly unveil the mechanism leading to the lower efficacy of PCSK9 mAb on LDL-cholesterol levels in women. Analysis of intact or ovariectomized PCSK9 knockout (KO) mice supplemented with placebo or 17ß-estradiol (E2) demonstrated that female, but not male mice massively shed the soluble ectodomain of the LDLR in the plasma. Liver-specific PCSK9 KO or alirocumab-treated WT mice exhibit the same pattern. This shedding is distinct from the basal one and is inhibited by ZLDI-8, a metalloprotease inhibitor pointing at ADAM10/ADAM17. In PCSK9 KO female mice, ZLDI-8 raises by 80â¯% the LDLR liver content in a few hours. This specific shedding is likely cholesterol-dependent: it is prevented in PCSK9 KO male mice that exhibit low intra-hepatic cholesterol levels without activating SREBP-2, and enhanced by mevalonate or high cholesterol feeding, or by E2 known to stimulate cholesterol synthesis via the estrogen receptor-α. Liver transcriptomics demonstrates that critically low liver cholesterol in ovariectomized female or knockout male mice also hampers the cholesterol-dependent G2/M transition of the cell cycle. Finally, higher levels of shed LDLR were measured in the plasma of women treated with PCSK9 mAb. PCSK9 knockout female mice hormonally sustain cholesterol synthesis and shed excess LDLR, seemingly like women. In contrast, male mice rely on high surface LDLR to replenish their stocks, despite 80â¯% lower circulating LDL.
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Ácido Mevalônico , Pró-Proteína Convertase 9 , Animais , Colesterol/metabolismo , Estradiol/metabolismo , Estradiol/farmacologia , Feminino , Fígado/metabolismo , Metaloproteases/metabolismo , Ácido Mevalônico/metabolismo , Camundongos , Camundongos Knockout , Pró-Proteína Convertase 9/metabolismo , Receptores de Superfície Celular , Receptores de Estrogênio , Receptores de LDL/genética , Receptores de LDL/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismoRESUMO
Previously, organophosphate flame retardants (OPFRs) were found to produce intersecting disruptions of energy homeostasis using an adult mouse model of diet-induced obesity. Using the same mixture consisting of 1 mg/kg/day of each triphenyl phosphate, tricresyl phosphate, and tris(1,3-dichloro-2-propyl)phosphate, the current study aimed to identify the role of estrogen receptor alpha (ERα) in OPFR-induced disruption, utilizing ERα knockout (ERαKO) mice fed either a low-fat diet (LFD) or high-fat diet (HFD). Body weight and composition, food intake patterns, glucose and insulin tolerance, circulating peptide hormones, and expression of hypothalamic genes associated with energy homeostasis were measured. When fed HFD, no marked direct effects of OPFR were observed in mice lacking ERα, suggesting a role for ERα in generating previously reported wildtype (WT) findings. Male ERαKO mice fed LFD experienced decreased feeding efficiency and altered insulin tolerance, whereas their female counterparts displayed less fat mass and circulating ghrelin when exposed to OPFRs. These effects were not noted in the previous WT study, indicating that loss of ERα may sensitize animals fed LFD to alternate pathways of endocrine disruption by OFPRs. Collectively, these data demonstrate both direct and indirect actions of OPFRs on ERα-mediated pathways governing energy homeostasis and support a growing body of evidence urging concern for risk of human exposure.
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Retardadores de Chama , Animais , Dieta Hiperlipídica/efeitos adversos , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Retardadores de Chama/toxicidade , Insulina , Masculino , Camundongos , Obesidade/induzido quimicamente , Obesidade/metabolismo , OrganofosfatosRESUMO
Women are more susceptible to functional bowel disorders than men and the severity of their symptoms such as diarrhea, constipation, abdominal pain and bloating changes over the menstrual cycle, suggesting a role for sex hormones in gastrointestinal function. Nitric oxide (NO) is a major inhibitory neurotransmitter in the gut and blockade of nitric oxide synthase (NOS; responsible for NO synthesis) increases colonic motility in male mice ex vivo. We assessed the effects of NOS inhibition on colonic motility in female mice using video imaging analysis of colonic motor complexes (CMCs). To understand interactions between NO and estrogen in the gut, we also quantified neuronal NOS and estrogen receptor alpha (ERα)-expressing myenteric neurons in estrus and proestrus female mice using immunofluorescence. Mice in estrus had fewer CMCs under control conditions (6 ± 1 per 15 min, n = 22) compared to proestrus (8 ± 1 per 15 min, n = 22, One-way ANOVA, p = 0.041). During proestrus, the NOS antagonist N-nitro-L-arginine (NOLA) increased CMC numbers compared to controls (189 ± 46%). In contrast, NOLA had no significant effect on CMC numbers during estrus. During estrus, we observed more NOS-expressing myenteric neurons (48 ± 2%) than during proestrus (39 ± 1%, n = 3, p = 0.035). Increased nuclear expression of ERα was observed in estrus which coincided with an altered motility response to NOLA in contrast with proestrus when ERα was largely cytoplasmic. In conclusion, we confirm a cyclic and sexually dimorphic effect of NOS activity in female mouse colon, which could be due to genomic effects of estrogens via ERα.
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There has been little progress for several decades in modalities to treat cervical cancer. While the cervix is a hormone-sensitive tissue, physiologic roles of estrogen receptor α (ERα), progesterone receptor (PR), and their ligands in this tissue are poorly understood. It has hampered critical assessments of data in early epidemiologic and clinical studies for cervical cancer. Experimental evidence obtained from studies using mouse models has provided new insights into the molecular mechanism of ERα and PR in cervical cancer. In a mouse model expressing human papillomavirus (HPV) oncogenes, exogenous estrogen promotes cervical cancer through stromal ERα. In the same mouse model, genetic ablation of PR promotes cervical carcinogenesis without exogenous estrogen. Medroxyprogesterone acetate, a PR-activating drug, regresses cervical cancer in the mouse model. These results support that ERα and PR play opposite roles in cervical cancer. They further support that ERα inhibition and PR activation may be translated into valuable treatment for a subset of cervical cancers.
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Neoplasias do Colo do Útero , Animais , Colo do Útero , Modelos Animais de Doenças , Estrogênios/uso terapêutico , Feminino , Hormônios Esteroides Gonadais/uso terapêutico , Humanos , Camundongos , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/genéticaRESUMO
Decrements in metabolic health elevate disease risk, including type 2 diabetes, heart disease, and certain cancers. Thus, treatment strategies to combat metabolic dysfunction are needed. Reduced ESR1 (estrogen receptor, ERα) expression is observed in muscle from women, men, and animals presenting clinical features of the metabolic syndrome. Human studies of natural expression of ESR1 in metabolic tissues show that muscle expression of ESR1 is positively correlated with markers of metabolic health, including insulin sensitivity. Herein, we highlight the important impact of ERα on mitochondrial form and function and present how these actions of the receptor govern metabolic homeostasis. Studies identifying ERα-regulated pathways for disease prevention will lay the foundation for the design of novel therapeutics to improve the health of women while limiting secondary complications that have plagued traditional hormone replacement interventions.
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Metabolismo Energético , Receptor alfa de Estrogênio/metabolismo , Homeostase , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Mitocôndrias/metabolismo , Animais , Suscetibilidade a Doenças , Receptor alfa de Estrogênio/genética , Humanos , Resistência à Insulina , Mitocôndrias/genética , Especificidade de ÓrgãosRESUMO
The estrogen receptor alpha (ERα) is expressed by the majority of breast cancers and plays an important role in breast cancer development and tumor outgrowth. Although ERα is well known to be a specific and efficient therapeutic target, the molecular mechanisms that are responsible for the control of ERα expression and function in the context of breast cancer initiation and progression are complex and not completely elucidated. In previous work, we have demonstrated that the tumor suppressor RASSF1A inhibits ERα expression and function in ERα-positive breast cancer cells through an AKT-dependent mechanism. Transcriptional activators such as forkhead box protein M1 (FOXM1) and forkhead transcription factor 3A (FOXO3A) and signaling pathways such as the Hippo pathway are also known to modulate ERα expression and activity. Here we report that RASSF1A acts as an inhibitor of ERα-driven breast cancer cell growth through a complex, hierarchically organized network that initially involves suppression of the Hippo effector Yes-associated protein 1 (YAP1), which is followed by inhibition of AKT1 activity, increased FOXO3A activity as well as a blockade of FOXM1 and ERα expression. Together our findings provide important new mechanistic insights into how the loss of RASSF1A contributes to ERα+ breast cancer initiation and progression.
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PURPOSE: The ETS transcription factor ESE-1 has been shown to be important in HER2+ breast cancer and ESE-1 mRNA expression has been shown to associate with prognostic outcomes in the HER2+ subtype, as well as in ER+, HER2+ luminal B patients. However, the clinical significance of ESE-1 protein expression remains unknown. The purpose of the current exploratory study is to evaluate the prognostic value of ESE-1 protein expression in molecular breast cancer subtypes with special emphasis on hormone receptor positive HER2+(HR+ HER2+) and the HER2 positive (HER2+-only) breast cancer patients. METHODS: We developed a mouse monoclonal anti-ESE-1 antibody, verified its specificity, epitope, and used immunohistochemical staining to assess ESE-1 expression in an IBC approved archive of 957 breast tumor samples. Using Pearson product correlation, contingency analysis, and long rank P value testing, we analyzed the association of ESE-1 expression with clinicopathological features and survival outcomes in HR+HER2-; HR+HER2+; HR- HER2- (Triple negative) and HR-HER2+ (HER2 subtype) patients. RESULTS: ESE-1, nuclear or cytoplasmic, was not significantly associated with survival outcomes in HR+HER2-, triple-negative, or HER2+-only breast cancer patients. However, high nuclear ESE-1 was associated with poor survival outcomes in hormone receptor positive (ERα+, PR+) HER2+ patients and was an independent prognostic marker for that group. CONCLUSIONS: This study provides evidence for prognostic significance of nuclear ESE-1 in ERalpha positive breast cancers patients also positive for HER2 indicating that crosstalk between ERalpha and ESE-1 in HER2+ tumors could be important for prognostic outcomes. Further studies regarding the nature of interaction between ESE-1 and ERalpha in these tumors are warranted.
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Neoplasias da Mama/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas Proto-Oncogênicas c-ets/metabolismo , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Fatores de Transcrição/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Prognóstico , Taxa de SobrevidaRESUMO
Background: Dysregulation of ESR1 accounts for endocrine therapy resistance and metastasis of ERα positive breast cancer. However, the underlying molecular mechanism of ESR1 in ERα positive breast cancer remains insufficiency. Notably, to date, a comprehensive miRNA-mRNA regulatory network involved in modulation of ESR1 in development and progression of ERα positive breast cancer is still not established. Methods: Microarray miRNA and mRNA expression profiling from GEO database were used to obtained significant DE-miRNAs and DE-mRNAs in ERα positive breast cancer. Functional enrichment analysis was conducted by Enrichr database. STRING database was utilized to construct protein-protein interaction network, after which hub genes were identified through Cytoscape. Kaplan-Meier plotter was introduced to perform survival analysis. The relationship between ESR1-miRNA or miRNA-target gene pairs were experimentally validated. Results: 74 DE-miRNAs, including 19 upregulated and 55 downregulated miRNAs, and 830 DE-mRNAs, including 359 upregulated and 471 downregulated mRNAs, in ERα positive breast cancer were identified. Potential DE-mRNAs were statistically enriched in several cancer-associated pathways, such as cell cycle and pathway in cancer. Fifty-one hub genes with node degree more than 10 were screened. Twenty-seven of 51 hub genes had significant prognostic values in ERα positive breast cancer. Based on the 27 hub genes, a miRNA-hub gene network, containing 26 miRNAs, was established. Seven of 26 miRNAs were found to possess prognostic predictive roles for patients with ERα positive breast cancer by combination of TCGA and METABRIC data. Intriguingly, ESR1 positively correlated and regulated the 7 miRNAs and the 7 miRNAs inversely correlated and modulated their corresponding downstream targets in MCF-7 and T47D cells, supporting the accuracy of in silico analysis. The relationship between ESR1-miRNA, miRNA-mRNA, or ESR1-mRNA pairs was validated in clinical ERα positive breast cancer. Conclusions: In total, the current findings from this work add substantially to the understanding of ESR1's molecular regulatory mechanism in ERα positive breast cancer.
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Benzimidazole is a valuable pharmacophore in the field of medicinal chemistry and exhibit wide spectrum of biological activity. Molecular docking technique is routinely used in modern drug discovery for understanding the drug-receptor interaction. The selected data set of synthesized benzimidazole compounds was evaluated for its in vitro anticancer activity against cancer cell lines (HCT116 and MCF7) by sulforhodamine B (SRB) assay. Further, molecular docking study of data set was carried out by Schrodinger-Maestro v11.5 using CDK-8 (PDB code: 5FGK) and ER-alpha (PDB code: 3ERT) as possible target for anticancer activity. Molecular docking results demonstrated that compounds 12, 16, N9, W20 and Z24 displayed good docking score with better interaction within crucial amino acids and corelate to their anticancer results. ADME results indicated that compounds 16, N9 and W20 have significant results within the close agreement of the Lipinski's rule of five and Qikprop rule within the range and these compounds may be taken as lead molecules for the discovery of new anticancer agents.
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INTRODUCTION: This study aimed to explore the role of vitamin D receptor (VDR) in breast cancer tissues and its relation to serum 25-hydroxyvitamin D [25(OH)D] levels and estrogen receptor alpha (ER-α) gene expression in patients with breast cancer. PATIENTS AND METHODS: Cancerous and normal breast tissues from 40 women with breast cancer were analyzed for quantification of VDR levels and ER-α gene expression. The serum levels of 25(OH)D were measured in patients with breast cancer and controls by radioimmunoassay. RESULTS: Patients with breast cancer had serum levels of 25(OH)D significantly lower than normal control subjects. The levels of VDR and ER-α were significantly higher in breast cancer tissues than in normal breast tissues. The serum levels of 25(OH)D were indirectly and significantly correlated with the tissue levels of both VDR and ER-α gene expression. There was a significant direct correlation between the tissue levels of VDR and ER-α gene expression. The serum 25(OH) D levels, tissue VDR levels, and ER-α gene expression levels were inversely and significantly correlated with breast cancer histopathologic grade. Women with serum 25(OH)D levels ≤ 30 nmol/L, tissue levels of VDR > 5 ng/mL, and tissue levels of ER-α gene expression > 17.7 copies had significantly increased risk for breast cancer incidence. CONCLUSION: Women with low serum 25(OH)D levels, high tissue levels of VDR, and ER-α gene expression had increased risk for breast cancer. VDR are upregulated in breast cancer tissues thus it may be used for target therapy especially in hormone-negative breast cancer.
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Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/metabolismo , Receptor alfa de Estrogênio/metabolismo , Receptores de Calcitriol/metabolismo , Vitamina D/análogos & derivados , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Egito/epidemiologia , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Incidência , Prognóstico , Curva ROC , Vitamina D/sangueRESUMO
The aim of the present study was to investigate the posttranscriptional regulation of bta-miR-222 and the estrogen receptor (ER)-alpha gene in cows. The preovulatory follicles (POFs) were detected and ER-alpha levels in the corpus luteum (CL) were measured via immunofluorescent method. Afterwards, an ELISA test was performed to detect estradiol- and progesterone-active follicles, and the expression levels of ER-alpha, progesterone receptor (PR), and bta-miR-222 were measured via qRT-PCR. Finally, a western blot analysis was performed to determine ER-alpha protein levels. Immunofluorescence staining was highly positive in the follicular phase, showing ER-alpha and PR immunopositivity. In the luteal phase, ER-alpha immunopositivity decreased in lutein cells, whereas the PRs were observed to be similar in intensity to those in follicular phase. While the estradiol levels were higher in the POFs, the progesterone level was higher in the CL. In the CL, the transcription levels of ER-alpha and PR mRNA were observed to be the same as in the POFs; however, the expression of bta-miR-222 was lower. In the CL, the transcription level of ER-alpha mRNA was lower than that of PR mRNA, and the expression level of bta-miR-222 was higher than that of PR mRNA. The results of the western blot analysis show that the ER-alpha protein level in the CL was lower than that in the POFs. Taken together, our results here suggest that there is a negative correlation between bta-miR-222 and ER-alpha expression during follicular development in cow ovaries.
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Receptor alfa de Estrogênio/metabolismo , MicroRNAs/metabolismo , Folículo Ovariano/metabolismo , Ovário/metabolismo , Animais , Bovinos , Corpo Lúteo/metabolismo , Receptor alfa de Estrogênio/genética , Feminino , Fase Folicular/metabolismo , Fase Luteal/metabolismo , MicroRNAs/genética , Progesterona/metabolismo , Receptores de Progesterona/metabolismoRESUMO
We investigated the expression of bcl-2, estrogen receptor alpha (ER-alpha), caspase-3, -8, -9, proliferating cell nuclear antigen (PCNA) and Ki-67 in canine mammary carcinomas. We used 65 paraffin embedded and re-diagnosed archival canine mammary tumor samples to which we applied the routine streptavidin-biotin-peroxidase technique. Seventeen cases were re-diagnosed as tubulopapillary carcinoma, 31 were re-diagnosed as complex carcinoma and 17 were re-diagnosed as carcinosarcoma. Differences of expression of bcl-2 and PCNA were statistically significant according to tumor type. Differences in expression of ER-alpha, caspase-3, -8, -9 and Ki-67 were not statistically significant. Differences of expression of bcl-2 and PCNA were statistically significant compared to ER-alpha, caspase-3, -8, -9 and Ki-67 in carcinosarcomas. We report the prognostic significance of bcl-2 and PCNA expression in canine mammary carcinosarcomas.
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Carcinoma/veterinária , Caspases/metabolismo , Receptor alfa de Estrogênio/metabolismo , Imuno-Histoquímica , Antígeno Ki-67/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Animais , Carcinoma/metabolismo , Carcinoma/patologia , Doenças do Cão/patologia , Cães , Feminino , Imuno-Histoquímica/métodos , Glândulas Mamárias Animais/patologia , Prognóstico , Antígeno Nuclear de Célula em Proliferação/metabolismoRESUMO
Aberrant expression of proteins often underlies many diseases, including cancer. A recently developed approach in drug development is small molecule-mediated, selective degradation of dysregulated proteins. We have devised a protein-knockdown system that utilizes chimeric molecules termed specific and nongenetic IAP-dependent protein erasers (SNIPERs) to induce ubiquitylation and proteasomal degradation of various target proteins. SNIPER(ER)-87 consists of an inhibitor of apoptosis protein (IAP) ligand LCL161 derivative that is conjugated to the estrogen receptor α (ERα) ligand 4-hydroxytamoxifen by a PEG linker, and we have previously reported that this SNIPER efficiently degrades the ERα protein. Here, we report that derivatization of the IAP ligand module yields SNIPER(ER)s with superior protein-knockdown activity. These improved SNIPER(ER)s exhibited higher binding affinities to IAPs and induced more potent degradation of ERα than does SNIPER(ER)-87. Further, they induced simultaneous degradation of cellular inhibitor of apoptosis protein 1 (cIAP1) and delayed degradation of X-linked IAP (XIAP). Notably, these reengineered SNIPER(ER)s efficiently induced apoptosis in MCF-7 human breast cancer cells that require IAPs for continued cellular survival. We found that one of these molecules, SNIPER(ER)-110, inhibits the growth of MCF-7 tumor xenografts in mice more potently than the previously characterized SNIPER(ER)-87. Mechanistic analysis revealed that our novel SNIPER(ER)s preferentially recruit XIAP, rather than cIAP1, to degrade ERα. Our results suggest that derivatized IAP ligands could facilitate further development of SNIPERs with potent protein-knockdown and cytocidal activities against cancer cells requiring IAPs for survival.
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Receptor alfa de Estrogênio/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Animais , Antineoplásicos/farmacologia , Regulação para Baixo , Humanos , Ligantes , Células MCF-7 , Camundongos , Ligação Proteica , Proteólise , Tiazóis/farmacologia , Ubiquitinação , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: We previously identified small molecules that fit into a BRCA1-binding pocket within estrogen receptor-alpha (ERα), mimic the ability of BRCA1 to inhibit ERα activity ("BRCA1-mimetics"), and overcome antiestrogen resistance. One such compound, the hydrochloride salt of NSC35446 ("NSC35446.HCl"), also inhibited the growth of antiestrogen-resistant LCC9 tumor xenografts. The purpose of this study was to investigate the down-stream effects of NSC35446.HCl and its mechanism of action. METHODS: Here, we studied antiestrogen-resistant (LCC9, T47DCO, MCF-7/RR, LY2), ERα-negative (MDA-MB-231, HCC1806, MDA-MB-468), and antiestrogen-sensitive (MCF-7) cell lines. Techniques utilized include RNA-seq, qRT-PCR, cell growth analysis, cell-cycle analysis, Western blotting, luciferase reporter assays, TUNEL assays, in silico analysis of the IKKB gene, and ChIP assays. RESULTS: SC35446.HCl inhibited proliferation and induced apoptosis in antiestrogen-resistant LCC9, T47DCO, MCF-7/RR, and LY2 cells but not in ERα-negative breast cancer cell lines. IKKB (IKKß, IKBKB), an upstream activator of NF-κB, was identified as a BRCA1-mimetic-regulated gene based on an RNA-seq analysis. NSC35446.HCl inhibited IKKB, IKKA, and IKKG/NEMO mRNA and protein expression in LCC9 cells. NSC35446.HCl also inhibited NF-κB activity and expression of NF-κB target genes. In silico analysis of the IKKB promoter identified nine estrogen response element (ERE) half-sites and one ERE-like full-site. ChIP assays revealed that ERα was recruited to the ERE-like full-site and five of the nine half-sites and that ERα recruitment was inhibited by NSC35446.HCl in LCC9 and T47DCO cells. CONCLUSIONS: These studies identify functional EREs in the IKKB promoter and identify IKKB as an ERα and NSC35446.HCl-regulated gene, and they suggest that NF-κB and IKKB, which were previously linked to antiestrogen resistance, are targets for NSC35446.HCl in reversing antiestrogen resistance.
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Neoplasias da Mama/tratamento farmacológico , Antagonistas de Estrogênios/administração & dosagem , Receptor alfa de Estrogênio/genética , Quinase I-kappa B/genética , Apoptose/genética , Proteína BRCA1/antagonistas & inibidores , Proteína BRCA1/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proliferação de Células/genética , Resistencia a Medicamentos Antineoplásicos/genética , Estrogênios/genética , Estrogênios/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , NF-kappa B/genética , Regiões Promotoras GenéticasRESUMO
BACKGROUND: Systemic lupus erythematosus (lupus) is a female predominant autoimmune disease. The autoreactive B cells and T helper cells together are known to develop adverse immune responses in different tissues like kidney, bone, cardiovascular and central nervous system. Progression of disease is associated with deposition of immune complex which initiates tissue damage. The therapy for lupus still includes corticosteroids to reduce allergic manifestations and inflammatory immune responses. Recent observations suggested that, mycophenolate mofetil and cyclophosphamide treatment in combination with corticosteroids have benefit in lupus therapy. METHOD: The prospect of B cell depletion by CD20 targeted monoclonal antibody Rituximab has been demonstrated in lupus patients. The CD52 specific monoclonal antibody Alemtuzumab is another proposition for lupus therapy. The drug Belimumab inhibits B cell activation by altering BAFF/APRIL signal cascade. Recent discovery of the CD22 targeted Epratuzumab also shows therapeutic prospect. The researches on new generation drugs for autoimmune lupus include search for inhibitors of CD40- CD40Ligand interactions, CD86 activation, selective modulation of complement cascades. The choice of inhibitors of transcription factor NF-κBp65 and selective modulators for estrogen receptor alpha are proposed areas of lupus drug discovery research. RESULTS & CONCLUSION: Keeping a close eye on the mechanisms of disease onset, a comprehensive view is provided on recent therapy of systemic lupus erythematosus.
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Corticosteroides/uso terapêutico , Ciclofosfamida/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Ácido Micofenólico/uso terapêutico , Animais , Descoberta de Drogas , Feminino , Humanos , Lúpus Eritematoso Sistêmico/imunologiaRESUMO
The PI3K/PTEN/AKT pathway is the most frequently mutated pathway in endometrial carcinoma. Mouse models are invaluable tools to understand, at the molecular level, the contributions of components of this pathway towards initiation and progression of endometrial carcinoma. This chapter summarizes results of germline and tissue specific knockout mouse models generated to understand how mutations in components of this pathway lead to development of carcinoma and its interactions with other frequently altered pathways like mismatch repair and estrogen signaling. The mouse models show that loss of both alleles of Pten is necessary and sufficient for complex atypical hyperplasia (CAH) to develop but insufficient for progression to carcinoma. Additional events like mutations in Pik3ca or mismatch repair deficiency are required for progression to carcinoma. The models show that the interaction between Pten and estrogen signaling is complex. In the absence of estrogen, Pten loss is sufficient for development of CAH. Additionally, lack of ERα on a background of Pten loss leads to the development of carcinoma.
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Neoplasias do Endométrio/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Classe I de Fosfatidilinositol 3-Quinases , Modelos Animais de Doenças , Neoplasias do Endométrio/genética , Feminino , Humanos , Camundongos , Camundongos Knockout , Mutação , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/genética , Transdução de Sinais/genéticaRESUMO
Targeted approaches have revealed frequent epigenetic alterations in ovarian cancer, but the scope and relation of these changes to histologic subtype of disease is unclear. Genome-wide methylation and expression data for 14 clear cell carcinoma (CCC), 32 non-CCC and four corresponding normal cell lines were generated to determine how methylation profiles differ between cells of different histological derivations of ovarian cancer. Consensus clustering showed that CCC is epigenetically distinct. Inverse relationships between expression and methylation in CCC were identified, suggesting functional regulation by methylation, and included 22 hypomethylated (UM) genes and 276 hypermethylated (HM) genes. Categorical and pathway analyses indicated that the CCC-specific UM genes were involved in response to stress and many contain hepatocyte nuclear factor (HNF) 1-binding sites, while the CCC-specific HM genes included members of the estrogen receptor alpha (ERalpha) network and genes involved in tumor development. We independently validated the methylation status of 17 of these pathway-specific genes, and confirmed increased expression of HNF1 network genes and repression of ERalpha pathway genes in CCC cell lines and primary cancer tissues relative to non-CCC specimens. Treatment of three CCC cell lines with the demethylating agent Decitabine significantly induced expression for all five genes analyzed. Coordinate changes in pathway expression were confirmed using two primary ovarian cancer datasets (p < 0.0001 for both). Our results suggest that methylation regulates specific pathways and biological functions in CCC, with hypomethylation influencing the characteristic biology of the disease while hypermethylation contributes to the carcinogenic process.
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Adenocarcinoma de Células Claras/genética , Metilação de DNA , Epigenômica , Neoplasias Ovarianas/genética , Adenocarcinoma de Células Claras/patologia , Feminino , Fator 1 Nuclear de Hepatócito/genética , Fator 1 Nuclear de Hepatócito/metabolismo , Humanos , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Reação em Cadeia da Polimerase em Tempo Real , Células Tumorais CultivadasRESUMO
During different stages of tumor development the immune system can either identify and destroy tumors, or promote their growth. Therapies targeting the immune system have emerged as a promising treatment modality for breast cancer, and immunotherapeutic strategies are being examined in preclinical and clinical models. However, our understanding of the complex interplay between cells of the immune system and breast cancer cells is incomplete. In this article, we review recent findings showing how the immune system plays dual host-protective and tumor-promoting roles in breast cancer initiation and progression. We then discuss estrogen receptor α (ERα)-dependent and ERα-independent mechanisms that shield breast cancers from immunosurveillance and enable breast cancer cells to evade immune cell induced apoptosis and produce an immunosuppressive tumor microenvironment. Finally, we discuss protumorigenic inflammation that is induced during tumor progression and therapy, and how inflammation promotes more aggressive phenotypes in ERα positive breast cancers.
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Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Sistema Imunitário/patologia , Inflamação/patologia , Carcinogênese/patologia , Feminino , Humanos , Evasão da Resposta Imune/imunologia , Microambiente Tumoral/imunologiaRESUMO
Osteoporosis is a complicated and preventable disease with major morbidity complications that affects millions of people. In the last 15 years, there have been numerous studies and research in the new fields of pharmacogenetics and pharmacogenomics related to osteoporosis. Numerous "candidate genes" have been identified and have been found to be associated with osteoporosis as well as the treatment of osteoporosis. Many studies have found conflicting results on different polymorphisms and whether or not they are related to bone mineral density and osteoporosis. There is a need for larger and better designed pharmacogenomic studies related to osteoporosis incorporating a greater variety of candidate genes. The evaluation of osteoporosis and fracture risk is moving from a risk stratification approach to a more individualized approach, in which an individual's absolute risk of fracture is evaluable as a constellation of the individual's environmental exposure and genetic makeup. Therefore, the identification of gene variants associated with osteoporosis phenotypes or response to therapy might help individualize the prognosis, treatment, and prevention of fracture. This review focuses on major candidate genes and what needs to be done to take the genetics of osteoporosis and incorporate them into the pharmacogenomics of the management of osteoporosis.