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1.
Acad Emerg Med ; 27(8): 742-752, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32030836

RESUMEN

BACKGROUND: Patients with chronic noncancer pain (CNCP) present unique challenges to emergency department (ED) care providers and administrators. Their conditions lead to frequent ED visits for pain relief and symptom management and are often poorly addressed with costly, low-yield care. A systematic review has not been performed to inform the management of frequent ED utilizing patients with CNCP. Therefore, we synthesized the available evidence on interventional strategies to improve care-associated outcomes for this patient group. METHODS: We searched Medline, EMBASE, CINAHL, CENTRAL, SCOPUS, and Web of Science from database inception to June 2018 for eligible interventional studies aimed at reducing frequent ED utilization among adult patients with CNCP. Articles were assessed in duplicate in accordance with methodologic recommendations from the Cochrane Handbook for Systematic Reviews of Interventions. Outcomes of interest were the frequency of subsequent ED visits, type and amount of opioids administered in the ED and prescribed at discharge, and costs. Methodologic quality was assessed using the Cochrane Risk of Bias in Non-Randomized Studies of Interventions and Risk of Bias tools for nonrandomized and randomized studies, respectively. RESULTS: Thirteen studies including 1,679 patients met the inclusion criteria. Identified interventions implemented pain policies (n = 4), individualized care plans (n = 5), ED care coordination (n = 2), chronic pain management pathways (n = 1), and behavioral health interventions (n = 1). All of the studies reported a decrease in ED visit frequency following their respective interventions. These reductions were especially pronounced in studies whose interventions were focused around individualized care plans and primary care involvement. Interventions implementing opioid restriction and pain management policies were largely successful in reducing the amounts of opioid medications administered and prescribed in the ED. CONCLUSIONS: Multifaceted interventions, especially those employing individualized care plans, can successfully reduce subsequent ED visits, ED opioid administration and prescription, and care-associated costs for frequent ED utilizing patients with CNCP.


Asunto(s)
Analgésicos Opioides , Dolor Crónico , Servicio de Urgencia en Hospital , Manejo del Dolor , Adulto , Analgésicos Opioides/uso terapéutico , Dolor Crónico/tratamiento farmacológico , Humanos , Alta del Paciente
2.
Histopathology ; 76(7): 976-987, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-31994214

RESUMEN

AIMS: Apolipoprotein D (ApoD) is a protein that is regulated by androgen and oestrogen, and is a major constituent of breast cysts. Although ApoD has been reported to be a marker of breast cancer, its prognostic importance in invasive breast cancer is unclear. The aim of this study was to investigate the relationship between ApoD protein expression, oestrogen receptor-α (ERα) expression and androgen receptor (AR) expression in predicting breast cancer outcome. METHODS AND RESULTS: ApoD levels were measured by the use of immunohistochemistry and video image analysis on tissue sections from a breast cancer cohort (n = 214). We assessed the associations of ApoD expression with disease-free survival (DFS), metastasis-free survival (MFS), and overall survival (OS). We also assessed the relationship between ApoD expression, AR expression and ERα expression in predicting OS. ApoD expression (>1% ApoD positivity) was found in 72% (154/214) of tissues. High ApoD positivity (≥20.7%, fourth quartile) was an independent predictor of MFS and OS, and conferred a 2.2-fold increased risk of developing metastatic disease and a 2.1-fold increased risk of breast cancer-related death. ApoD positivity was not associated with AR or ERα nuclear positivity. However, patients with (≥1%) ERα-positive cancers with low (<20.7%) ApoD positivity, or those showing high (≥78%) AR positivity and low (<20.7%) ApoD positivity had better OS than other patient groups. CONCLUSIONS: ApoD expression could be used to predict breast cancer prognosis independently of ERα and AR expression.


Asunto(s)
Apolipoproteínas D/metabolismo , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/patología , Adulto , Apolipoproteínas D/análisis , Femenino , Humanos , Persona de Mediana Edad , Pronóstico , Resultado del Tratamiento
3.
Clin Cancer Res ; 24(10): 2328-2341, 2018 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-29514843

RESUMEN

Purpose: Consensus is lacking regarding the androgen receptor (AR) as a prognostic marker in breast cancer. The objectives of this study were to comprehensively review the literature on AR prognostication and determine optimal criteria for AR as an independent predictor of breast cancer survival.Experimental Design: AR positivity was assessed by immunostaining in two clinically validated primary breast cancer cohorts [training cohort, n = 219; validation cohort, n = 418; 77% and 79% estrogen receptor alpha (ERα) positive, respectively]. The optimal AR cut-point was determined by ROC analysis in the training cohort and applied to both cohorts.Results: AR was an independent prognostic marker of breast cancer outcome in 22 of 46 (48%) previous studies that performed multivariate analyses. Most studies used cut-points of 1% or 10% nuclear positivity. Herein, neither 1% nor 10% cut-points were robustly prognostic. ROC analysis revealed that a higher AR cut-point (78% positivity) provided optimal sensitivity and specificity to predict breast cancer survival in the training (HR, 0.41; P = 0.015) and validation (HR, 0.50; P = 0.014) cohorts. Tenfold cross-validation confirmed the robustness of this AR cut-point. Patients with ERα-positive tumors and AR positivity ≥78% had the best survival in both cohorts (P < 0.0001). Among the combined ERα-positive cases, those with comparable or higher levels of AR (AR:ERα-positivity ratio >0.87) had the best outcomes (P < 0.0001).Conclusions: This study defines an optimal AR cut-point to reliably predict breast cancer survival. Testing this cut-point in prospective cohorts is warranted for implementation of AR as a prognostic factor in the clinical management of breast cancer. Clin Cancer Res; 24(10); 2328-41. ©2018 AACR.


Asunto(s)
Biomarcadores de Tumor , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Receptores Androgénicos/metabolismo , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/terapia , Quimioterapia Adyuvante , Estudios de Cohortes , Femenino , Humanos , Estimación de Kaplan-Meier , Pronóstico , Curva ROC , Receptores Androgénicos/sangre , Receptores de Estrógenos/metabolismo , Reproducibilidad de los Resultados
4.
Int J Oncol ; 46(5): 2223-30, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25695794

RESUMEN

Despite incremental advances in the diagnosis and treatment for pancreatic cancer (PC), the 5­year survival rate remains <5%. Novel therapies to increase survival and quality of life for PC patients are desperately needed. Epigenetic thera-peutic agents such as histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors (DNMTi) have demonstrated therapeutic benefits in human cancer. We assessed the efficacy of these epigenetic therapeutic agents as potential therapies for PC using in vitro and in vivo models. Treatment with HDACi [suberoylanilide hydroxamic acid (SAHA)] and DNMTi [5­AZA­2' deoxycytidine (5­AZA­dc)] decreased cell proliferation in MiaPaCa2 cells, and SAHA treatment, with or without 5­AZA­dc, resulted in higher cell death and lower DNA synthesis compared to 5­AZA­dc alone and controls (DMSO). Further, combination treatment with SAHA and 5­AZA­dc significantly increased expression of p21WAF1, leading to G1 arrest. Treatment with epigenetic agents delayed tumour growth in vivo, but did not decrease growth of established pancreatic tumours. In conclusion, these data demonstrate a potential role for epigenetic modifier drugs for the management of PC, specifically in the chemoprevention of PC, in combination with other chemotherapeutic agents.


Asunto(s)
Antineoplásicos/farmacología , Azacitidina/análogos & derivados , Proliferación Celular/efectos de los fármacos , Ácidos Hidroxámicos/farmacología , Neoplasias Pancreáticas/patología , Animales , Azacitidina/farmacología , Western Blotting , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Decitabina , Modelos Animales de Enfermedad , Femenino , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Vorinostat
5.
BMC Genomics ; 15: 476, 2014 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-24929644

RESUMEN

BACKGROUND: Free circulating DNA (fcDNA) has many potential clinical applications, due to the non-invasive way in which it is collected. However, because of the low concentration of fcDNA in blood, genome-wide analysis carries many technical challenges that must be overcome before fcDNA studies can reach their full potential. There are currently no definitive standards for fcDNA collection, processing and whole-genome sequencing. We report novel detailed methodology for the capture of high-quality methylated fcDNA, library preparation and downstream genome-wide Next-Generation Sequencing. We also describe the effects of sample storage, processing and scaling on fcDNA recovery and quality. RESULTS: Use of serum versus plasma, and storage of blood prior to separation resulted in genomic DNA contamination, likely due to leukocyte lysis. Methylated fcDNA fragments were isolated from 5 donors using a methyl-binding protein-based protocol and appear as a discrete band of ~180 bases. This discrete band allows minimal sample loss at the size restriction step in library preparation for Next-Generation Sequencing, allowing for high-quality sequencing from minimal amounts of fcDNA. Following sequencing, we obtained 37 × 10(6)-86 × 10(6) unique mappable reads, representing more than 50% of total mappable reads. The methylation status of 9 genomic regions as determined by DNA capture and sequencing was independently validated by clonal bisulphite sequencing. CONCLUSIONS: Our optimized methods provide high-quality methylated fcDNA suitable for whole-genome sequencing, and allow good library complexity and accurate sequencing, despite using less than half of the recommended minimum input DNA.


Asunto(s)
Metilación de ADN , ADN/sangre , ADN/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Anciano , Composición de Base , ADN/química , ADN/aislamiento & purificación , Contaminación de ADN , Femenino , Biblioteca de Genes , Voluntarios Sanos , Humanos , Persona de Mediana Edad , Reproducibilidad de los Resultados , Factores de Riesgo , Análisis de Secuencia de ADN
6.
J Bone Miner Res ; 29(9): 1938-49, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24676805

RESUMEN

The bone microenvironment and its modification by cancer and host cell interactions is a key driver of skeletal metastatic growth. Interleukin-6 (IL-6) stimulates receptor activator of NF-κB ligand (RANKL) expression in bone cells, and serum IL-6 levels are associated with poor clinical outcomes in cancer patients. We investigated the effects of RANKL on cancer cells and the role of tumor-derived IL-6 within the bone microenvironment. Using human breast cancer cell lines to induce tumors in the bone of immune-deficient mice, we first determined whether RANKL released by cells of the osteoblast lineage directly promotes IL-6 expression by cancer cells in vitro and in vivo. We then disrupted of IL-6 signaling in vivo either via knockdown of IL-6 in tumor cells or through treatment with specific anti-human or anti-mouse IL-6 receptor antibodies to investigate the tumor effect. Finally, we tested the effect of RANK knockdown in cancer cells on cancer growth. We demonstrate that osteoblast lineage-derived RANKL upregulates secretion of IL-6 by breast cancers in vivo and in vitro. IL-6, in turn, induces expression of RANK by cancer cells, which sensitizes the tumor to RANKL and significantly enhances cancer IL-6 release. Disruption in vivo of this auto-amplifying crosstalk by knockdown of IL-6 or RANK in cancer cells, or via treatment with anti-IL-6 receptor antibodies, significantly reduces tumor growth in bone but not in soft tissues. RANKL and IL-6 mediate direct paracrine-autocrine signaling between cells of the osteoblast lineage and cancer cells, significantly enhancing the growth of metastatic breast cancers within bone.


Asunto(s)
Neoplasias Óseas/secundario , Linaje de la Célula , Interleucina-6/metabolismo , Neoplasias/patología , Osteoblastos/patología , Ligando RANK/metabolismo , Transducción de Señal , Animales , Neoplasias Óseas/patología , Resorción Ósea/patología , Huesos/efectos de los fármacos , Huesos/metabolismo , Huesos/patología , Línea Celular Tumoral , Linaje de la Célula/efectos de los fármacos , Técnicas de Cocultivo , Progresión de la Enfermedad , Técnicas de Silenciamiento del Gen , Humanos , Ratones , Metástasis de la Neoplasia , Neoplasias/sangre , Osteoblastos/efectos de los fármacos , Ligando RANK/sangre , Receptor Activador del Factor Nuclear kappa-B/metabolismo , Receptores de Interleucina-6/metabolismo , Proteínas Recombinantes/farmacología , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
7.
BMC Cancer ; 14: 32, 2014 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-24444383

RESUMEN

BACKGROUND: Although MYC is an attractive therapeutic target for breast cancer treatment, it has proven challenging to inhibit MYC directly, and clinically effective pharmaceutical agents targeting MYC are not yet available. An alternative approach is to identify genes that are synthetically lethal in MYC-dependent cancer. Recent studies have identified several cell cycle kinases as MYC synthetic-lethal genes. We therefore investigated the therapeutic potential of specific cyclin-dependent kinase (CDK) inhibition in MYC-driven breast cancer. METHODS: Using small interfering RNA (siRNA), MYC expression was depleted in 26 human breast cancer cell lines and cell proliferation evaluated by BrdU incorporation. MYC-dependent and MYC-independent cell lines were classified based on their sensitivity to siRNA-mediated MYC knockdown. We then inhibited CDKs including CDK4/6, CDK2 and CDK1 individually using either RNAi or small molecule inhibitors, and compared sensitivity to CDK inhibition with MYC dependence in breast cancer cells. RESULTS: Breast cancer cells displayed a wide range of sensitivity to siRNA-mediated MYC knockdown. The sensitivity was correlated with MYC protein expression and MYC phosphorylation level. Sensitivity to siRNA-mediated MYC knockdown did not parallel sensitivity to the CDK4/6 inhibitor PD0332991; instead MYC-independent cell lines were generally sensitive to PD0332991. Cell cycle arrest induced by MYC knockdown was accompanied by a decrease in CDK2 activity, but inactivation of CDK2 did not selectively affect the viability of MYC-dependent breast cancer cells. In contrast, CDK1 inactivation significantly induced apoptosis and reduced viability of MYC-dependent cells but not MYC- independent cells. This selective induction of apoptosis by CDK1 inhibitors was associated with up-regulation of the pro-apoptotic molecule BIM and was p53-independent. CONCLUSIONS: Overall, these results suggest that further investigation of CDK1 inhibition as a potential therapy for MYC-dependent breast cancer is warranted.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/enzimología , Proteína Quinasa CDC2/antagonistas & inhibidores , Quinasa 2 Dependiente de la Ciclina/metabolismo , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Terapia Molecular Dirigida , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Interferencia de ARN , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteína 11 Similar a Bcl2 , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Proteína Quinasa CDC2/genética , Proteína Quinasa CDC2/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 2 Dependiente de la Ciclina/genética , Quinasa 4 Dependiente de la Ciclina/genética , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/genética , Quinasa 6 Dependiente de la Ciclina/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Proteínas de la Membrana/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Transducción de Señal/efectos de los fármacos , Transfección , Proteína p53 Supresora de Tumor/metabolismo
8.
Mol Cancer ; 13: 3, 2014 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-24393131

RESUMEN

BACKGROUND: We previously identified that the CpG island-associated promoter of the novel lincRNA ZNF300P1 (also known as LOC134466) is frequently hypermethylated and silenced in ovarian cancer tissues. However, the function of ZNF300P1 was unknown. In this report we demonstrate that ZNF300P1 is involved in the regulation of key cell cycle and cell motility networks in human ovarian surface epithelial cells, and may play a role in promoting metastasis in ovarian cancer cells. METHODS: We applied methylated DNA immunoprecipitation on whole genome promoter tiling arrays and Sequenom assays to examine methylation status of ZNF300P1 in multiple ovarian cancer cell lines, as well as in normal ovarian and ovarian tumor tissues. Transcript profiling was used to investigate the effects of ZNF300P1 suppression in ovarian cancer cells. We utilized siRNA knockdown in normal ovarian surface epithelial cells and performed cellular proliferation, migration and adhesion assays to validate and explore the profiling results. RESULTS: We demonstrate that ZNF300P1 is methylated in multiple ovarian cancer cell lines. Loss of ZNF300P1 results in decreased cell proliferation and colony formation. In addition, knockdown of the ZNF300P1 transcript results in aberrant and less persistent migration in wound healing assays due to a loss of cellular polarity. Using an ex vivo peritoneal adhesion assay, we also reveal a role for ZNF300P1 in the attachment of ovarian cancer cells to peritoneal membranes, indicating a potential function of ZNF300P1 expression in metastasis of ovarian cancer cells to sites within the peritoneal cavity. CONCLUSION: Our findings further support ZNF300P1 as frequently methylated in ovarian cancer and reveal a novel function for ZNF300P1 lincRNA expression in regulating cell polarity, motility, and adhesion and loss of expression may contribute to the metastatic potential of ovarian cancer cells.


Asunto(s)
Polaridad Celular/genética , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Ováricas/genética , ARN Largo no Codificante/genética , Proteínas Represoras/genética , Carcinoma Epitelial de Ovario , Adhesión Celular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular , Metilación de ADN/genética , Epigénesis Genética/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Humanos , Inmunoprecipitación , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción
9.
J Clin Invest ; 123(7): 2893-906, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23921126

RESUMEN

Host response to cancer signals has emerged as a key factor in cancer development; however, the underlying molecular mechanism is not well understood. In this report, we demonstrate that activating transcription factor 3 (ATF3), a hub of the cellular adaptive response network, plays an important role in host cells to enhance breast cancer metastasis. Immunohistochemical analysis of patient tumor samples revealed that expression of ATF3 in stromal mononuclear cells, but not cancer epithelial cells, is correlated with worse clinical outcomes and is an independent predictor for breast cancer death. This finding was corroborated by data from mouse models showing less efficient breast cancer metastasis in Atf3-deficient mice than in WT mice. Further, mice with myeloid cell-selective KO of Atf3 showed fewer lung metastases, indicating that host ATF3 facilitates metastasis, at least in part, by its function in macrophage/myeloid cells. Gene profiling analyses of macrophages from mouse tumors identified an ATF3-regulated gene signature that could distinguish human tumor stroma from distant stroma and could predict clinical outcomes, lending credence to our mouse models. In conclusion, we identified ATF3 as a regulator in myeloid cells that enhances breast cancer metastasis and has predictive value for clinical outcomes.


Asunto(s)
Factor de Transcripción Activador 3/fisiología , Inmunidad Adaptativa , Neoplasias de la Mama/metabolismo , Neoplasias Pulmonares/metabolismo , Animales , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Movimiento Celular , Técnicas de Cocultivo , Femenino , Expresión Génica , Regulación Neoplásica de la Expresión Génica , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/secundario , Macrófagos/inmunología , Macrófagos/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Análisis Multivariante , Trasplante de Neoplasias , Células Neoplásicas Circulantes , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Análisis de Matrices Tisulares , Transcriptoma , Carga Tumoral , Células Tumorales Cultivadas
10.
FEBS J ; 280(21): 5237-57, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23876235

RESUMEN

Acquired resistance to the anti-estrogen tamoxifen remains a significant challenge in breast cancer management. In this study, we used an integrative approach to characterize global protein expression and tyrosine phosphorylation events in tamoxifen-resistant MCF7 breast cancer cells (TamR) compared with parental controls. Quantitative mass spectrometry and computational approaches were combined to identify perturbed signalling networks, and candidate regulatory proteins were functionally interrogated by siRNA-mediated knockdown. Network analysis revealed that cellular metabolism was perturbed in TamR cells, together with pathways enriched for proteins associated with growth factor, cell-cell and cell matrix-initiated signalling. Consistent with known roles for Ras/MAPK and PI3-kinase signalling in tamoxifen resistance, tyrosine-phosphorylated MAPK1, SHC1 and PIK3R2 were elevated in TamR cells. Phosphorylation of the tyrosine kinase Yes and expression of the actin-binding protein myristoylated alanine-rich C-kinase substrate (MARCKS) were increased two- and eightfold in TamR cells respectively, and these proteins were selected for further analysis. Knockdown of either protein in TamR cells had no effect on anti-estrogen sensitivity, but significantly decreased cell motility. MARCKS expression was significantly higher in breast cancer cell lines than normal mammary epithelial cells and in ER-negative versus ER-positive breast cancer cell lines. In primary breast cancers, cytoplasmic MARCKS staining was significantly higher in basal-like and HER2 cancers than in luminal cancers, and was independently predictive of poor survival in multivariate analyses of the whole cohort (P < 0.0001) and in ER-positive patients (P = 0.0005). These findings provide network-level insights into the molecular alterations associated with the tamoxifen-resistant phenotype, and identify MARCKS as a potential biomarker of therapeutic responsiveness that may assist in stratification of patients for optimal therapy.


Asunto(s)
Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Resistencia a Antineoplásicos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de la Membrana/metabolismo , Fosfoproteínas/metabolismo , Tamoxifeno/farmacología , Antineoplásicos Hormonales/farmacología , Apoptosis , Western Blotting , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/patología , Adhesión Celular , Ciclo Celular , Movimiento Celular , Proliferación Celular , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Técnicas para Inmunoenzimas , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas de la Membrana/genética , Persona de Mediana Edad , Sustrato de la Proteína Quinasa C Rico en Alanina Miristoilada , Fosforilación/efectos de los fármacos , Mapas de Interacción de Proteínas , Proteómica , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Análisis de Matrices Tisulares , Células Tumorales Cultivadas
11.
Cancer Res ; 73(14): 4474-87, 2013 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-23720052

RESUMEN

Although ERBB2 amplification and overexpression is correlated with poor outcome in breast cancer, the molecular mechanisms underlying the aggressive nature of these tumors has not been fully elucidated. To investigate this further, we have used a transgenic mouse model of ErbB2-driven tumor progression (ErbB2(KI) model) that recapitulates clinically relevant events, including selective amplification of the core erbB2 amplicon. By comparing the transcriptional profiles of ErbB2(KI) mammary tumors and human ERBB2-positive breast cancers, we show that ErbB2(KI) tumors possess molecular features of the basal subtype of ERBB2-positive human breast cancer, including activation of canonical ß-catenin signaling. Inhibition of ß-catenin-dependent signaling in ErbB2(KI)-derived tumor cells using RNA interference impaired tumor initiation and metastasis. Furthermore, treatment of ErbB2(KI) or human ERBB2-overexpressing tumor cells with a selective ß-catenin/CBP inhibitor significantly decreased proliferation and ErbB2 expression. Collectively, our data indicate that ERBB2-mediated breast cancer progression requires ß-catenin signaling and can be therapeutically targeted by selective ß-catenin/CBP inhibitors.


Asunto(s)
Neoplasias de la Mama/patología , Neoplasias Mamarias Experimentales/patología , Receptor ErbB-2/metabolismo , beta Catenina/metabolismo , Animales , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Proliferación Celular , Progresión de la Enfermedad , Regulación hacia Abajo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Células MCF-7 , Neoplasias Mamarias Experimentales/enzimología , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/metabolismo , Ratones , Receptor ErbB-2/genética , Transducción de Señal , Transcripción Genética , beta Catenina/genética
12.
BJU Int ; 112(5): 585-93, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23551500

RESUMEN

OBJECTIVE: To present the template-guided transperineal prostate biopsy (TPB) outcomes for patients of two urologists from a single institution. PATIENTS AND METHODS: We conducted a prospective study of 409 consecutive men who underwent TPB between December 2006 and June 2008 in a tertiary referral centre using a standardized 14-region technique. The procedure was performed as day surgery under general anaesthesia with fluoroquinolone antibiotic cover. Follow-up took place within 2 weeks, during which time men were interviewed using a standardized template. Results were compared with those of the Australian national prostate biopsy audits performed by the Urological Society of Australia and New Zealand (USANZ). RESULTS: Indications for biopsy included elevated prostate-specific antigen (PSA) level (75%), with a median PSA level of 6.5 ng/mL, abnormal digital rectal examination (8%) and active surveillance (AS) re-staging (18%). The mean patient age was 63 years and two-thirds of patients were undergoing their first biopsy. A positive biopsy was found in 232 men, 74% of whom had a Gleason score of ≥7. The overall cancer detection rate was 56.7% (USANZ 2005 national audit = 56.5%). Stratified between those having their first TPB or a repeat procedure (after a previous negative biopsy), the detection rates were 64.4 and 35.6%, respectively. Significantly higher detection rates were found in prostates <50 mL in volume than in larger prostates (65.2 vs 38.3%, respectively, P < 0.001). Haematuria was the most common side effect (51.7%). Others included dysuria (16.4%), acute urinary retention (4.2%) and fever (3.2%). One patient (0.2%) had septicaemia requiring i.v. antibiotics. Repeat biopsy was not associated with increased complication rates. CONCLUSIONS: TPB is a safe and efficacious technique, with a cancer detection rate of 56.7% in the present series, and a low incidence of major side effects. Stratified by prostate volume, the detection rate of TPB was higher in smaller glands. Given the relatively low rate of serious complications, clinicians could consider increasing the number of TPB biopsy cores in larger prostates as a strategy to improve cancer detection within this group. Conversely, in patients on AS programmes, a staging TPB may be a superior approach for patients undergoing repeat biopsy so as to minimize their risk of serious infection.


Asunto(s)
Biopsia con Aguja/efectos adversos , Próstata/patología , Neoplasias de la Próstata/patología , Enfermedades del Recto/microbiología , Recto/microbiología , Anciano , Procedimientos Quirúrgicos Ambulatorios , Antibacterianos/administración & dosificación , Detección Precoz del Cáncer , Estudios de Seguimiento , Humanos , Masculino , Evaluación de Resultado en la Atención de Salud , Perineo , Estudios Prospectivos , Enfermedades del Recto/prevención & control
13.
J Clin Oncol ; 31(10): 1348-56, 2013 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-23439753

RESUMEN

PURPOSE: Individuals with adenocarcinoma of the ampulla of Vater demonstrate a broad range of outcomes, presumably because these cancers may arise from any one of the three epithelia that converge at that location. This variability poses challenges for clinical decision making and the development of novel therapeutic strategies. PATIENTS AND METHODS: We assessed the potential clinical utility of histomolecular phenotypes defined using a combination of histopathology and protein expression (CDX2 and MUC1) in 208 patients from three independent cohorts who underwent surgical resection for adenocarcinoma of the ampulla of Vater. RESULTS: Histologic subtype and CDX2 and MUC1 expression were significant prognostic variables. Patients with a histomolecular pancreaticobiliary phenotype (CDX2 negative, MUC1 positive) segregated into a poor prognostic group in the training (hazard ratio [HR], 3.34; 95% CI, 1.69 to 6.62; P < .001) and both validation cohorts (HR, 5.65; 95% CI, 2.77 to 11.5; P < .001 and HR, 2.78; 95% CI, 1.25 to 7.17; P = .0119) compared with histomolecular nonpancreaticobiliary carcinomas. Further stratification by lymph node (LN) status defined three clinically relevant subgroups: one, patients with histomolecular nonpancreaticobiliary (intestinal) carcinoma without LN metastases who had an excellent prognosis; two, those with histomolecular pancreaticobiliary carcinoma with LN metastases who had a poor outcome; and three, the remainder of patients (nonpancreaticobiliary, LN positive or pancreaticobiliary, LN negative) who had an intermediate outcome. CONCLUSION: Histopathologic and molecular criteria combine to define clinically relevant histomolecular phenotypes of adenocarcinoma of the ampulla of Vater and potentially represent distinct diseases with significant implications for current therapeutic strategies, the ability to interpret past clinical trials, and future trial design.


Asunto(s)
Adenocarcinoma/metabolismo , Ampolla Hepatopancreática/metabolismo , Neoplasias del Conducto Colédoco/metabolismo , Proteínas de Homeodominio/biosíntesis , Mucina-1/biosíntesis , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Ampolla Hepatopancreática/patología , Factor de Transcripción CDX2 , Estudios de Cohortes , Neoplasias del Conducto Colédoco/patología , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Queratina-20/biosíntesis , Queratina-7/biosíntesis , Masculino , Persona de Mediana Edad , Mucina 2/biosíntesis , Análisis Multivariante , Estadificación de Neoplasias , Pronóstico
14.
Cell Cycle ; 12(4): 606-17, 2013 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-23324395

RESUMEN

Cyclins E1 drives the initiation of DNA replication, and deregulation of its periodic expression leads to mitotic delay associated with genomic instability. Since it is not known whether the closely related protein cyclin E2 shares these properties, we overexpressed cyclin E2 in breast cancer cells. This did not affect the duration of mitosis, nor did it cause an increase in p107 association with CDK2. In contrast, cyclin E1 overexpression led to inhibition of the APC complex, prolonged metaphase and increased p107 association with CDK2. Despite these different effects on the cell cycle, elevated levels of either cyclin E1 or E2 led to hallmarks of genomic instability, i.e., an increased proportion of abnormal mitoses, micronuclei and chromosomal aberrations. Cyclin E2 induction of genomic instability by a mechanism distinct from cyclin E1 indicates that these two proteins have unique functions in a cancer setting.


Asunto(s)
Ciclina E/genética , Ciclinas/genética , Regulación Neoplásica de la Expresión Génica , Mitosis , Proteínas Oncogénicas/genética , Línea Celular Tumoral , Ciclina E/metabolismo , Quinasa 2 Dependiente de la Ciclina/genética , Quinasa 2 Dependiente de la Ciclina/metabolismo , Ciclinas/metabolismo , Replicación del ADN , Genoma Humano , Inestabilidad Genómica , Humanos , Metafase , Micronúcleos con Defecto Cromosómico , Microscopía Fluorescente , Proteínas Oncogénicas/metabolismo , Proteína p107 Similar a la del Retinoblastoma/genética , Proteína p107 Similar a la del Retinoblastoma/metabolismo
15.
Cell Cycle ; 12(4): 596-605, 2013 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-23324394

RESUMEN

Cyclin E1 is expressed at the G 1/S phase transition of the cell cycle to drive the initiation of DNA replication and is degraded during S/G2M. Deregulation of its periodic degradation is observed in cancer and is associated with increased proliferation and genomic instability. We identify that in cancer cells, unlike normal cells, the closely related protein cyclin E2 is expressed predominantly in S phase, concurrent with DNA replication. This occurs at least in part because the ubiquitin ligase component that is responsible for cyclin E1 downregulation in S phase, Fbw7, fails to effectively target cyclin E2 for proteosomal degradation. The distinct cell cycle expression of the two E-type cyclins in cancer cells has implications for their roles in genomic instability and proliferation and may explain their associations with different signatures of disease.


Asunto(s)
Proteínas de Ciclo Celular/genética , Ciclina E/genética , Ciclinas/genética , Proteínas F-Box/genética , Puntos de Control de la Fase G1 del Ciclo Celular/genética , Puntos de Control de la Fase G2 del Ciclo Celular/genética , Regulación Neoplásica de la Expresión Génica , Proteínas Oncogénicas/genética , Ubiquitina-Proteína Ligasas/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Ciclina E/metabolismo , Ciclinas/metabolismo , Replicación del ADN , Proteínas F-Box/metabolismo , Proteína 7 que Contiene Repeticiones F-Box-WD , Genoma Humano , Inestabilidad Genómica , Humanos , Proteínas Oncogénicas/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteolisis , Ubiquitina-Proteína Ligasas/metabolismo
16.
J Bone Oncol ; 2(1): 47-57, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26909265

RESUMEN

The bone microenvironment provides a fertile soil for cancer cells. It is therefore not surprising that the skeleton is a frequent site of cancer metastasis. It is believed that reciprocal interactions between tumour and bone cells, known as the "vicious cycle of bone metastasis" support the establishment and orchestrate the expansion of malignant cancers in bone. While the full range of molecular mechanisms of cancer metastasis to bone remain to be elucidated, recent research has deepened our understanding of the cell-mediated processes that may be involved in cancer cell survival and growth in bone. This review aims to address the importance of the bone microenvironment in skeletal cancer metastasis and discusses potential therapeutic implications of novel insights.

17.
Mol Cell Biol ; 33(3): 557-70, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23166300

RESUMEN

Tyrosine phosphorylation-dependent signaling, as mediated by members of the epidermal growth factor receptor (EGFR) family (ErbB1 to -4) of protein tyrosine kinases (PTKs), Src family PTKs (SFKs), and cytokines such as interleukin-6 (IL-6) that signal via signal transducer and activator of transcription 3 (STAT3), is critical to the development and progression of many human breast cancers. EGFR, SFKs, and STAT3 can serve as substrates for the protein tyrosine phosphatase TCPTP (PTPN2). Here we report that TCPTP protein levels are decreased in a subset of breast cancer cell lines in vitro and that TCPTP protein is absent in a large proportion of "triple-negative" primary human breast cancers. Homozygous TCPTP deficiency in murine mammary fat pads in vivo is associated with elevated SFK and STAT3 signaling, whereas TCPTP deficiency in human breast cancer cell lines enhances SFK and STAT3 signaling. On the other hand, TCPTP reconstitution in human breast cancer cell lines severely impaired cell proliferation and suppressed anchorage-independent growth in vitro and xenograft growth in vivo. These studies establish TCPTP's potential to serve as a tumor suppressor in human breast cancer.


Asunto(s)
Neoplasias de la Mama/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 2/metabolismo , Factor de Transcripción STAT3/metabolismo , Familia-src Quinasas/metabolismo , Animales , Mama/metabolismo , Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Ratones , Ratones Endogámicos C57BL , Proteína Tirosina Fosfatasa no Receptora Tipo 2/genética , Transducción de Señal
18.
Cancer Cell ; 23(1): 9-22, 2013 Jan 14.
Artículo en Inglés | MEDLINE | ID: mdl-23245995

RESUMEN

Epigenetic gene deregulation in cancer commonly occurs through chromatin repression and promoter hypermethylation of tumor-associated genes. However, the mechanism underpinning epigenetic-based gene activation in carcinogenesis is still poorly understood. Here, we identify a mechanism of domain gene deregulation through coordinated long-range epigenetic activation (LREA) of regions that typically span 1 Mb and harbor key oncogenes, microRNAs, and cancer biomarker genes. Gene promoters within LREA domains are characterized by a gain of active chromatin marks and a loss of repressive marks. Notably, although promoter hypomethylation is uncommon, we show that extensive DNA hypermethylation of CpG islands or "CpG-island borders" is strongly related to cancer-specific gene activation or differential promoter usage. These findings have wide ramifications for cancer diagnosis, progression, and epigenetic-based gene therapies.


Asunto(s)
Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Genoma , Neoplasias de la Próstata/genética , Línea Celular Tumoral , Islas de CpG , Metilación de ADN , Histonas/metabolismo , Humanos , Masculino , MicroARNs/genética , MicroARNs/fisiología , Regiones Promotoras Genéticas
19.
BJU Int ; 110 Suppl 4: 71-6, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23194129

RESUMEN

OBJECTIVE: • To compare long-term biochemical control of high-risk prostate cancer in those men receiving high-dose rate brachytherapy (HDRB) and radical prostatectomy (RP). PATIENTS AND METHODS: • The 10-year biochemical freedom from relapse (BFR) was calculated for 243 patients who underwent either RP or combined therapy with HDRB + external beam radiotherapy + androgen deprivation between 1998 and 2000. • INCLUSION CRITERIA: clinical stage ≥ T2b, or Gleason sum ≥ 8, or PSA level of > 20 ng/mL. Groups were appraised using the Kattan nomogram for surgery to calculate progression-free probability (PFP). RESULTS: • For the RP group (153 patients) the median PSA level was 8.1 ng/mL and the median age was 62.2 years. The median 5- and 10-year predicted PFP for RP was 64% and 56 %, respectively. The 5- and 10-year BFR was 65.5% and 55.4%. There was no significant difference between the predicted and the actual PFP for the RP group (P= 0.525). • For HDRB group (90 patients). The median PSA level was 14.2 ng/mL and the median age was 67.6 years. The median 5- and 10-year predicted PFP for HDRB was 46% and 35%, respectively. The 5- and 10-year BFR was 79.6% and 53.6%. There was a significant improvement between the actual and the predicted PFP for the HDRB group (P= 0.002). CONCLUSIONS: • Amongst a high-risk cohort, patients undergoing RP performed as predicted by the pre-treatment surgical nomogram, whereas the patients undergoing HDRB performed significantly better than was predicted by the surgical nomogram at 10 years.


Asunto(s)
Braquiterapia/métodos , Estadificación de Neoplasias , Antígeno Prostático Específico/sangre , Próstata/patología , Prostatectomía/métodos , Neoplasias de la Próstata/radioterapia , Anciano , Biopsia , Supervivencia sin Enfermedad , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/cirugía , Dosificación Radioterapéutica , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento
20.
Breast Cancer Res ; 14(6): R143, 2012 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-23127292

RESUMEN

INTRODUCTION: The prognostic significance of p53 protein expression in early breast cancer remains uncertain, with some but not all studies finding an association with poorer outcomes. Estrogen receptor (ER) expression is both a positive prognostic marker and predictive of response to endocrine therapies. The relationship between these biomarkers is unknown. METHODS: We constructed tissue microarrays (TMAs) from available pathological material from 1113 patients participating in two randomized clinical trials comparing endocrine therapy alone versus chemo-endocrine therapy in node-negative breast cancer. Expression of p53 defined as >10% positive nuclei was analyzed together with prior immunohistochemical assays of ER performed at central pathological review of whole tumor sections. RESULTS: ER was present (i.e. >1% positive tumor cell nuclei) in 80.1% (880/1092). p53 expression was significantly more frequent when ER was absent, 125/212 (59%) than when ER was present, 171/880 (19%), p <0.0001. A significant qualitative interaction was observed such that p53 expression was associated with better disease-free survival (DFS) and overall survival (OS) among patients whose tumors did not express ER, but worse DFS and OS among patients whose tumors expressed ER. The interaction remained significant after allowance for pathologic variables, and treatment. Similar effects were seen when luminal and non-luminal intrinsic subtypes were compared. CONCLUSIONS: Interpretation of the prognostic significance of p53 expression requires knowledge of concurrent expression of ER. The reason for the interaction between p53 and ER is unknown but may reflect qualitatively different p53 mutations underlying the p53 expression in tumors with or without ER expression. TRIAL REGISTRATION: Current Controlled Trials ACTRN12607000037404 (Trial VIII) and ACTRN12607000029493 (Trial IX).


Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Receptores de Estrógenos/biosíntesis , Tamoxifeno/uso terapéutico , Proteína p53 Supresora de Tumor/biosíntesis , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/biosíntesis , Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Ciclofosfamida/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/uso terapéutico , Goserelina/uso terapéutico , Humanos , Ganglios Linfáticos , Metotrexato/uso terapéutico , Persona de Mediana Edad , Análisis de Matrices Tisulares , Resultado del Tratamiento
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