RESUMO
BACKGROUND: Preclinical studies have demonstrated that propranolol inhibits several pathways involved in breast cancer progression and metastasis. We investigated whether breast cancer patients who used propranolol, or other non-selective beta-blockers, had reduced breast cancer-specific or all-cause mortality in eight European cohorts. METHODS: Incident breast cancer patients were identified from eight cancer registries and compiled through the European Cancer Pharmacoepidemiology Network. Propranolol and non-selective beta-blocker use was ascertained for each patient. Breast cancer-specific and all-cause mortality were available for five and eight cohorts, respectively. Cox regression models were used to calculate hazard ratios (HR) and 95% confidence intervals (CIs) for cancer-specific and all-cause mortality by propranolol and non-selective beta-blocker use. HRs were pooled across cohorts using meta-analysis techniques. Dose-response analyses by number of prescriptions were also performed. Analyses were repeated investigating propranolol use before cancer diagnosis. RESULTS: The combined study population included 55,252 and 133,251 breast cancer patients in the analysis of breast cancer-specific and all-cause mortality respectively. Overall, there was no association between propranolol use after diagnosis of breast cancer and breast cancer-specific or all-cause mortality (fully adjusted HR = 0.94, 95% CI, 0.77, 1.16 and HR = 1.09, 95% CI, 0.93, 1.28, respectively). There was little evidence of a dose-response relationship. There was also no association between propranolol use before breast cancer diagnosis and breast cancer-specific or all-cause mortality (fully adjusted HR = 1.03, 95% CI, 0.86, 1.22 and HR = 1.02, 95% CI, 0.94, 1.10, respectively). Similar null associations were observed for non-selective beta-blockers. CONCLUSIONS: In this large pooled analysis of breast cancer patients, use of propranolol or non-selective beta-blockers was not associated with improved survival.
Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Inibidores da Angiogênese/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Propranolol/uso terapêutico , Neoplasias da Mama/mortalidade , Estudos de Coortes , Europa (Continente) , Feminino , Humanos , Modelos de Riscos Proporcionais , Resultado do TratamentoRESUMO
BACKGROUND & AIMS: Individuals who began taking low-dose aspirin before they were diagnosed with colorectal cancer were reported to have longer survival times than patients who did not take this drug. We investigated survival times of patients who begin taking low-dose aspirin after a diagnosis of colorectal cancer in a large population-based cohort study. METHODS: We performed a nested case-control analysis using a cohort of 4794 patients diagnosed with colorectal cancer from 1998 through 2007, identified from the UK Clinical Practice Research Datalink and confirmed by cancer registries. There were 1559 colorectal cancer-specific deaths, recorded by the Office of National Statistics; these were each matched with up to 5 risk-set controls. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI), based on practitioner-recorded aspirin usage. RESULTS: Overall, low-dose aspirin use after a diagnosis of colorectal cancer was not associated with colorectal cancer-specific mortality (adjusted OR = 1.06; 95% CI: 0.92-1.24) or all-cause mortality (adjusted OR = 1.06; 95% CI: 0.94-1.19). A dose-response association was not apparent; for example, low-dose aspirin use for more than 1 year after diagnosis was not associated with colorectal cancer-specific mortality (adjusted OR = 0.98; 95% CI: 0.82-1.19). There was also no association between low-dose aspirin usage and colon cancer-specific mortality (adjusted OR = 1.02; 95% CI: 0.83-1.25) or rectal cancer-specific mortality (adjusted OR = 1.10; 95% CI: 0.88-1.38). CONCLUSIONS: In a large population-based cohort, low-dose aspirin usage after diagnosis of colorectal cancer did not increase survival time.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Aspirina/uso terapêutico , Neoplasias Colorretais/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Estudos de Coortes , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fatores de Risco , Taxa de SobrevidaRESUMO
INTRODUCTION: Recent observational studies indicate that post-diagnostic use of aspirin in breast cancer patients may protect against cancer progression perhaps by inhibiting cyclooxygenase-2 dependent mechanisms. Evidence also supports a crucial role for interactions between tumour cells and circulating platelets in cancer growth and dissemination, therefore, use of low-dose aspirin may reduce the risk of death from cancer in breast cancer patients. METHODS: A cohort of newly diagnosed breast cancer patients (1998 to 2006) were identified in the UK Clinical Practice Research Datalink (and confirmed by cancer registry linkage). Cancer-specific deaths were identified up to 2011 from Office for National Statistics mortality data. A nested case-control analysis was conducted using conditional logistic regression to compare post-diagnostic aspirin exposure using General Practice prescription data in 1,435 cases (breast cancer deaths) with 5,697 controls (matched by age and year of diagnosis). RESULTS: After breast cancer diagnosis, 18.3% of cancer-specific deaths and 18.5% of matched controls received at least one prescription for low-dose aspirin, corresponding to an odds ratio (OR) of 0.98 (95% CI 0.83, 1.15). Adjustment for potential confounders (including stage and grade) had little impact on this estimate. No dose response relationship was observed when the number of tablets was investigated and no associations were seen when analyses were stratified by receipt of prescriptions for aspirin in the pre-diagnostic period, by stage at diagnosis or by receipt of prescriptions for hormone therapy. CONCLUSIONS: Overall, in this large population-based cohort of breast cancer patients, there was little evidence of an association between receipt of post-diagnostic prescriptions for low-dose aspirin and breast cancer-specific death. However, information was not available on medication compliance or over-the-counter use of aspirin, which may have contributed to the null findings.
Assuntos
Aspirina/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Prescrições de Medicamentos/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Pesquisa Biomédica/estatística & dados numéricos , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/mortalidade , Estudos de Casos e Controles , Estudos de Coortes , Inibidores de Ciclo-Oxigenase/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Taxa de Sobrevida , Fatores de Tempo , Reino UnidoRESUMO
PURPOSE: Aspirin use is associated with reduced risk of, and death from, prostate cancer. Our aim was to determine whether low-dose aspirin use after a prostate cancer diagnosis was associated with reduced prostate cancer-specific mortality. METHODS: A cohort of newly diagnosed prostate cancer patients (1998-2006) was identified in the UK Clinical Practice Research Datalink (confirmed by cancer registry linkage). A nested case-control analysis was conducted using conditional logistic regression to compare aspirin usage in cases (prostate cancer deaths) with up to three controls (matched by age and year of diagnosis). RESULTS: Post-diagnostic low-dose aspirin use was identified in 52 % of 1,184 prostate cancer-specific deaths and 39 % of 3,531 matched controls (unadjusted OR 1.51, 95 % CI 1.19, 1.90; p < 0.001). After adjustment for confounders including treatment and comorbidities, this association was attenuated (adjusted OR 1.02 95 % CI 0.78, 1.34; p = 0.86). Adjustment for estrogen therapy accounted for the majority of this attenuation. There was also no evidence of dose-response association after adjustments. Compared with no use, patients with 1-11 prescriptions and 12 or more prescriptions had adjusted ORs of 1.07 (95 % CI 0.78, 1.47; p = 0.66) and 0.97 (95 % CI 0.69, 1.37; p = 0.88), respectively. There was no evidence of a protective association between low-dose aspirin use in the year prior to diagnosis and prostate cancer-specific mortality (adjusted OR 1.04 95 % CI 0.89, 1.22; p = 0.60). CONCLUSION: We found no evidence of an association between low-dose aspirin use before or after diagnosis and risk of prostate cancer-specific mortality, after potential confounders were accounted for, in UK prostate cancer patients.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Aspirina/administração & dosagem , Neoplasias da Próstata/mortalidade , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Humanos , Masculino , Pessoa de Meia-Idade , Risco , Reino UnidoRESUMO
Breast cancer is a heterogeneous and complex disease. Although the use of tumor biomarkers has improved individualized breast cancer care, i.e., assessment of risk, diagnosis, prognosis, and prediction of treatment outcome, new markers are required to further improve patient clinical management. In the present study, a search for novel breast cancer-associated genes was performed by mining the UniGene database for expressed sequence tags (ESTs) originating from human normal breast, breast cancer tissue, or breast cancer cell lines. Two hundred and twenty-eight distinct breast-associated UniGene Clusters (BUC1-228) matched the search criteria. Four BUC ESTs (BUC6, BUC9, BUC10, and BUC11) were subsequently selected for extensive in silico database searches, and in vitro analyses through sequencing and RT-PCR based assays on well-characterized cell lines and tissues of normal and cancerous origin. BUC6, BUC9, BUC10, and BUC11 are clustered on 10p11.21-12.1 and showed no homology to any known RNAs. Overall, expression of the four BUC transcripts was high in normal breast and testis tissue, and in some breast cancers; in contrast, BUC was low in other normal tissues, peripheral blood mononuclear cells (PBMCs), and other cancer cell lines. Results to-date suggest that BUC11 and BUC9 translate to protein and BUC11 cytoplasmic and nuclear protein expression was detected in a large cohort of breast cancer samples using immunohistochemistry. This study demonstrates the discovery and expression analysis of a tissue-restricted novel transcript set which is strongly expressed in breast tissue and their application as clinical cancer biomarkers clearly warrants further investigation.
Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/genética , Mama/metabolismo , Perfilação da Expressão Gênica , Transcriptoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Processamento Alternativo , Azacitidina/farmacologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Biologia Computacional , Mineração de Dados , Bases de Dados de Ácidos Nucleicos , Etiquetas de Sequências Expressas , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Transcrição GênicaRESUMO
Ubiquitin-positive intraneuronal inclusions are a consistent feature of the major human neurodegenerative diseases, suggesting that dysfunction of the ubiquitin proteasome system is central to disease etiology. Research using inhibitors of the 20S proteasome to model Parkinson's disease is controversial. We report for the first time that specifically 26S proteasomal dysfunction is sufficient to trigger neurodegenerative disease. Here, we describe novel conditional genetic mouse models using the Cre/loxP system to spatially restrict inactivation of Psmc1 (Rpt2/S4) to neurons of either the substantia nigra or forebrain (e.g., cortex, hippocampus, and striatum). PSMC1 is an essential subunit of the 26S proteasome and Psmc1 conditional knock-out mice display 26S proteasome depletion in targeted neurons, in which the 20S proteasome is not affected. Impairment of specifically ubiquitin-mediated protein degradation caused intraneuronal Lewy-like inclusions and extensive neurodegeneration in the nigrostriatal pathway and forebrain regions. Ubiquitin and alpha-synuclein neuropathology was evident, similar to human Lewy bodies, but interestingly, inclusion bodies contained mitochondria. We support this observation by demonstrating mitochondria in an early form of Lewy body (pale body) from Parkinson's disease patients. The results directly confirm that 26S dysfunction in neurons is involved in the pathology of neurodegenerative disease. The model demonstrates that 26S proteasomes are necessary for normal neuronal homeostasis and that 20S proteasome activity is insufficient for neuronal survival. Finally, we are providing the first reproducible genetic platform for identifying new therapeutic targets to slow or prevent neurodegeneration.
Assuntos
Encéfalo/enzimologia , Corpos de Inclusão/enzimologia , Corpos de Lewy/enzimologia , Degeneração Neural/enzimologia , Degeneração Neural/genética , Neurônios/enzimologia , Complexo de Endopeptidases do Proteassoma/deficiência , Animais , Encéfalo/patologia , Feminino , Humanos , Corpos de Inclusão/genética , Corpos de Inclusão/patologia , Corpos de Lewy/genética , Corpos de Lewy/patologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Degeneração Neural/patologia , Neurônios/patologia , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/fisiologiaRESUMO
AIM: In 2005 we reported the discovery of a novel anatomical structure at the limbus, which we termed the limbal epithelial crypt (LEC). The purpose of this study was to further evaluate the distribution, immunophenotypical, and ultra structural characteristics of the LEC as a putative niche of stem cells. METHODS: Sequential histological sections of human corneo-scleral limbal rims were examined for the presence and distribution of the LEC. Immunophenotypical characterisation of the LEC cells using a panel of antibodies of interest was undertaken. Transmission electron microscopy of the LEC was used to examine the ultra structural and morphometric features of cells within the LEC and adjacent limbus. RESULTS: A total of 74 LECs were identified in eight corneo-scleral rims. These varied in number, size and distribution within rims. Cells within the crypt demonstrated the following phenotype: CK3-/CK19+/CD 34-/Vimentin+/p63+/Connexin 43+/MIB1 (Ki67)-. Presence of Cx43 was also demonstrated in the rete pegs adjacent to the LEC. Basal cells of the LEC were significantly smaller than basal cells found in adjacent rete pegs and also smaller than suprabasal limbal and central corneal epithelial cells (p<0.05). Morphologically they had a high nuclear:cytoplasmic ratio and were adherent to the underlying basement membrane by means of complex convolutions of cytoplasmic processes. CONCLUSIONS: LECs are sparse but a consistent finding in the human corneo-scleral limbus. The LEC contains a unique sub-population of cells expressing several characteristics that are consistent with it representing a putative stem cell niche.
Assuntos
Epitélio Corneano/ultraestrutura , Limbo da Córnea/ultraestrutura , Tamanho Celular , Conexina 43/metabolismo , Epitélio Corneano/imunologia , Epitélio Corneano/metabolismo , Humanos , Técnicas Imunoenzimáticas , Imunofenotipagem , Proteínas de Filamentos Intermediários/metabolismo , Limbo da Córnea/imunologia , Limbo da Córnea/metabolismo , Proteínas de Membrana/metabolismo , Microscopia Eletrônica , Células-Tronco/metabolismo , Células-Tronco/ultraestruturaRESUMO
PURPOSE: To study the involvement of apoptosis using different apoptosis markers in PVR pathogenesis. METHODS: The presence of mRNA coding for Fas, Fas ligand (FasL), and TNF-related apoptosis inducing ligand (TRAIL) was investigated in vitreous samples from 46 consecutive patients-25 with PVR, 11 with retinal detachment (RD) not complicated by PVR, and 10 with macular hole (MH)-using RT-PCR. From previously examined vitreous samples, 21 PVR, 9 RD, and 10 MH were examined for their levels of TGF-beta2 protein with sandwich ELISA kits. Five epiretinal membranes excised from five patients with PVR were also examined for apoptotic cell death using the terminal deoxytransferase (TdT) mediated dUTP-biotin nick end labeling (TUNEL) technique. RESULTS: FAS mRNA was detected in 72% of patients with PVR, 55% of patients with RD and 20% of patients with MH. TRAIL mRNA was detected in 67% of patients with PVR, 89% of patients with RD, and 20% of patients with MH. FasL mRNA was detected in 20% of patients with PVR, 9% of patients with RD, and 10% of patients with MH. The median levels of Fas and TRAIL mRNA were significantly higher (P < 0.05) in patients with PVR than in those with MH hole but between patients with PVR and those with RD the difference was not significant (P > 0.05). A significant difference was detected between RD and MH for TRAIL mRNA levels (P = 0.008). For FasL, no significant difference between groups was found. TGF-beta2 was detected in all investigated vitreous samples. A significant difference was found between the PVR and MH groups (P = 0.001) and between the RD and MH groups (P = 0.004), but not between the PVR and RD groups (P < 0.05). The level of TGF-beta2 was significantly correlated to the level of TRAIL mRNA (r = 0.86), but no correlation was found between TGF-beta2 and Fas mRNA levels (r = 0.21). Four of five examined PVR epiretinal membranes showed positive staining for apoptotic cells using the TUNEL technique. CONCLUSIONS: Apoptosis is one of the mechanisms that is involved in PVR pathogenesis. Different apoptosis markers suggest different pathways occur in PVR, including Fas/FasL, TRAIL, and TGF-beta2 mediated processes.
Assuntos
Apoptose , Vitreorretinopatia Proliferativa/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Reguladoras de Apoptose , Biomarcadores/análise , Ensaio de Imunoadsorção Enzimática , Membrana Epirretiniana/patologia , Proteína Ligante Fas , Feminino , Humanos , Marcação In Situ das Extremidades Cortadas , Masculino , Glicoproteínas de Membrana/genética , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Descolamento Retiniano/metabolismo , Descolamento Retiniano/patologia , Perfurações Retinianas/metabolismo , Perfurações Retinianas/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ligante Indutor de Apoptose Relacionado a TNF , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta2 , Fator de Necrose Tumoral alfa/genética , Regulação para Cima , Vitreorretinopatia Proliferativa/metabolismo , Corpo Vítreo/metabolismo , Receptor fas/genéticaRESUMO
BACKGROUND: Recent laboratory and epidemiological evidence suggests that beta-blockers could inhibit prostate cancer progression. METHODS: We investigated the effect of beta-blockers on prostate cancer-specific mortality in a cohort of prostate cancer patients. Prostate cancer patients diagnosed between 1998 and 2006 were identified from the UK Clinical Practice Research Database and confirmed by cancer registries. Patients were followed up to 2011 with deaths identified by the Office of National Statistics. A nested case-control analysis compared patients dying from prostate cancer (cases) with up to three controls alive at the time of their death, matched by age and year of diagnosis. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression. RESULTS: Post-diagnostic beta-blocker use was identified in 25% of 1184 prostate cancer-specific deaths and 26% of 3531 matched controls. There was little evidence (P=0.40) of a reduction in the risk of cancer-specific death in beta-blocker users compared with non-users (OR=0.94 95% CI 0.81, 1.09). Similar results were observed after adjustments for confounders, in analyses by beta-blocker frequency, duration, type and for all-cause mortality. CONCLUSIONS: Beta-blocker usage after diagnosis was not associated with cancer-specific or all-cause mortality in prostate cancer patients in this large UK study.
Assuntos
Antagonistas Adrenérgicos beta/administração & dosagem , Neoplasias da Próstata/mortalidade , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/tratamento farmacológico , Análise de Sobrevida , Reino Unido/epidemiologiaRESUMO
BACKGROUND: To investigate the association between post-diagnostic beta-blocker usage and risk of cancer-specific mortality in a large population-based cohort of female breast cancer patients. METHODS: A nested case-control study was conducted within a cohort of breast cancer patients identified from cancer registries in England(using the National Cancer Data repository) and diagnosed between 1998 and 2007. Patients who had a breast cancer-specific death(ascertained from Office of National Statistics death registration data) were each matched to four alive controls by year and age at diagnosis. Prescription data for these patients were available through the Clinical Practice Research Datalink. Conditional logistic regression models were used to investigate the association between breast cancer-specific death and beta-blocker usage. RESULTS: Post-diagnostic use of beta-blockers was identified in 18.9% of 1435 breast cancer-specific deaths and 19.4% of their 5697 matched controls,indicating little evidence of association between beta-blocker use and breast cancer-specific mortality [odds ratio (OR) = 0.97,95% confidence interval (CI) 0.83, 1.13]. There was also little evidence of an association when analyses were restricted to cardio non-selective beta-blockers (OR = 0.90, 95% CI 0.69, 1.17). Similar results were observed in analyses of drug dosage frequency and duration, and beta-blocker type. CONCLUSIONS: In this large UK population-based cohort of breast cancer patients,there was little evidence of an association between post-diagnostic beta-blocker usage and breast cancer progression. Further studies which include information on tumour receptor status are warranted to determine whether response to beta-blockers varies by tumour subtypes.
Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Neoplasias da Mama/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Reino UnidoRESUMO
MicroRNAs (miRNAs) are a class of small endogenous non-coding RNAs that regulate gene expression post-transcriptionally through targeting protein-coding mRNAs for cleavage or translational repression, and thus play key roles in cellular fate-determinant pathways. Both profiling and functional studies demonstrated derangement of miRNA repertoire in many human cancers, including breast tumours. Discovery of miRNAs provided new insights into cancer pathogenesis and led the scientific community to approach novel diagnostic and therapeutic strategies in cancer management. Research in this field is increasing, and the potential for miRNAs being used in clinical settings emphasises the need for high-throughput and sensitive detection techniques. In this chapter, techniques for the analysis of miRNA expression in laser-microdissected formalin-fixed paraffin-embedded breast cancer tissues are discussed.
Assuntos
Neoplasias da Mama/genética , Lasers , MicroRNAs/isolamento & purificação , Microdissecção/métodos , Adulto , Neoplasias da Mama/patologia , Desoxirribonucleases/química , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Limite de Detecção , MicroRNAs/química , MicroRNAs/genética , Microtomia/métodos , Pessoa de Meia-Idade , Invasividade Neoplásica , Inclusão em Parafina , Reação em Cadeia da Polimerase/métodos , Kit de Reagentes para DiagnósticoRESUMO
BACKGROUND: Although virtually all cases of lobular carcinoma in situ lack E-cadherin expression, a proportion of morphologically typical invasive lobular carcinomas (ILCs) retain its expression. The frequency and significance of E-cadherin expression in ILC remain to be elucidated. In this study, we have assessed E-cadherin protein expression in a well-characterized series of histologically defined ILC (239 cases) with a long-term clinical follow-up to determine the frequency, clinical and biological significance of its expression. E-cadherin-positive ILCs (ILC+) were subsequently examined to assess the expression of component members of the E-cadherin membrane complex (E-cadherin, p120, α, ß, and γ-catenins) to determine its integrity. RESULTS: Thirty-eight ILC cases (16%) showed positive E-cadherin expression (ILC+). Membranous expression of E-cadherin was mainly circumferential with frequent coexisting perimembranous cytoplasmic expression. No association between E-cadherin expression and any of the clinicopathologic variables, immunophenotype, or tumor behavior was identified, apart from an association with lobular histologic subtype and vascular invasion. Analysis of the E-cadherin-catenin complex showed abnormal expression of one or more of the catenin complex members in the majority of cases. The most frequent observation was the diffuse cytoplasmic expression of catenins, in particular p120, which showed similar expression to that reported in E-cadherin-negative ILCs. CONCLUSIONS: These results provide evidence that E-cadherin is expressed in a proportion of ILC, however, unlike ductal carcinoma, its expression seems to be of limited significance and it is usually associated with evidence of impaired integrity of the E-cadherin-catenin membrane complex. Our data offer a possible explanation for the presence but lack functionality of E-cadherin in some cases of ILC and imply that immunohistochemical expression of E-cadherin per se in ILC histologic phenotypic tumors should not preclude its diagnosis.
Assuntos
Neoplasias da Mama/metabolismo , Caderinas/metabolismo , Carcinoma Lobular/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Carcinoma Lobular/patologia , Feminino , Humanos , Linfonodos/patologia , Menopausa , Pessoa de Meia-Idade , Invasividade NeoplásicaRESUMO
Post-translational histone modifications are known to be altered in cancer cells, and loss of selected histone acetylation and methylation marks has recently been shown to predict patient outcome in human carcinoma. Immunohistochemistry was used to detect a series of histone lysine acetylation (H3K9ac, H3K18ac, H4K12ac, and H4K16ac), lysine methylation (H3K4me2 and H4K20me3), and arginine methylation (H4R3me2) marks in a well-characterized series of human breast carcinomas (n = 880). Tissue staining intensities were assessed using blinded semiquantitative scoring. Validation studies were done using immunofluorescence staining and Western blotting. Our analyses revealed low or absent H4K16ac in the majority of breast cancer cases (78.9%), suggesting that this alteration may represent an early sign of breast cancer. There was a highly significant correlation between histone modifications status, tumor biomarker phenotype, and clinical outcome, where high relative levels of global histone acetylation and methylation were associated with a favorable prognosis and detected almost exclusively in luminal-like breast tumors (93%). Moderate to low levels of lysine acetylation (H3K9ac, H3K18ac, and H4K12ac), lysine (H3K4me2 and H4K20me3), and arginine methylation (H4R3me2) were observed in carcinomas of poorer prognostic subtypes, including basal carcinomas and HER-2-positive tumors. Clustering analysis identified three groups of histone displaying distinct pattern in breast cancer, which have distinct relationships to known prognostic factors and clinical outcome. This study identifies the presence of variations in global levels of histone marks in different grades, morphologic types, and phenotype classes of invasive breast cancer and shows that these differences have clinical significance.
Assuntos
Biomarcadores Tumorais/metabolismo , Histonas/metabolismo , Acetilação , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Análise por Conglomerados , Feminino , Histonas/genética , Humanos , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Metilação , Análise em Microsséries , Invasividade Neoplásica , Fenótipo , PrognósticoRESUMO
Loss of heterozygosity on the long arm of chromosome 16 is one of the most frequent genetic events in breast cancer, suggesting the presence of one or more classic tumor-suppressor genes (TSGs). It has been shown that E-cadherin is the TSG on 16q in lobular tumors. In a search for the target genes in more frequently occurring low-grade nonlobular tumors, the smallest region of overlap (SRO) in this area of the genome has been exhaustively searched for. However, the results have demonstrated remarkable complexity, and so a clear consensus on identification of the SRO boundaries has not been reached. Several genes in the vicinity of these SROs have been scrutinized as putative TSGs in breast cancer, but so far, none has fulfilled the criteria for target genes. This review discusses the complexity of the 16q region and the different approaches that have been, are being, and will be used to detect the target genes in this area.