RESUMO
OBJECTIVE@#To examine the expressions of JMJD3, matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF) in invasive ductal breast carcinoma, their association with the clinicopathological features of the patients and the effect of JMJD3 overexpression on proliferation and MMP-2 and VEGF expressions in breast cancer cells.@*METHODS@#The protein and mRNA expressions of JMJD3, MMP-2, and VEGF in invasive ductal breast carcinoma and paired adjacent tissues were detected by immunohistochemistry and RT-PCR, respectively, and their correlation with the clinicopathological characteristics of the patients was analyzed. Kaplan-Meier survival analysis was used to evaluate the correlation of JMJD3, MMP-2 and VEGF expression levels with the survival of the patients. In breast cancer MDA-MB-231 cells transfected with a JMJD3-expression plasmid, the expression of Ki67 was examined immunohistochemically, the cell proliferation was assessed with CCK8 assay, and the mRNA expressions of MMP-2 and VEGF were detected with RT-PCR.@*RESULTS@#Breast cancer tissues had significantly lower JMJD3 expression and higher MMP-2 and VEGF expressions at both the mRNA and protein levels than the adjacent tissue (@*CONCLUSIONS@#The expressions of JMJD3, MMP-2 and VEGF in invasive ductal breast carcinoma are closely correlated to tumor proliferation, invasion, metastasis and prognosis and can be used for prognostic evaluation of breast cancer.
Assuntos
Humanos , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Histona Desmetilases com o Domínio Jumonji , Metástase Linfática , Metaloproteinase 2 da Matriz , Prognóstico , Fator A de Crescimento do Endotélio VascularRESUMO
RESUMEN Introducción. La cadherina E (CDH1) cumple un papel importante en la transición epitelio-mesénquima y está relacionada con la invasión y las metástasis en varios tipos de carcinomas. Sin embargo, el efecto de las mutaciones y 'epimutaciones' germinales en la propensión al cáncer de mama no es claro. Objetivo. Evaluar el polimorfismo rs5030625, los cambios en el patrón de metilación del promotor y la expresión en la transcripción del gen CDH1 en pacientes con cáncer de mama. Materiales y métodos. Se tomaron muestras de sangre periférica de 102 pacientes con cáncer de mama y 102 mujeres de control. La genotipificación del polimorfismo rs5030625 se hizo mediante reacción en cadena de la polimerasa (PCR) y análisis de polimorfismos de longitud del fragmento de restricción; la PCR y el análisis de disociación de alta resolución sensible a metilación se emplearon para determinar el estado y el nivel de metilación del promotor del CDH1; por último, el nivel de expresión en la transcripción del CDH1 se evaluó mediante PCR cuantitativa con transcripción inversa. Resultados. Los resultados no evidenciaron asociación entre el polimorfismo rs5030625 y el cáncer de mama. Se encontraron perfiles aberrantes de metilación del promotor del CDH1 en las pacientes con cáncer de mama relacionados con las primeras etapas de desarrollo del cáncer. La disminución de la expresión del CDH1 se asoció con la presencia de metástasis y el estado de metilación del promotor. Conclusión. Las alteraciones en el CDH1 se asociaron con la invasión y las metástasis en el cáncer de mama. Se proporcionó evidencia adicional sobre la relevancia del CDH1 en el desarrollo y la progresión del cáncer de mama.
ABSTRACT Introduction: Cadherin-E (CDH1) is an important regulator of epithelial-mesenchymal transition, invasion and metastasis in many carcinomas. However, germinal epimutations and mutations effect in breast cancer susceptibility is not clear. Objective: To evaluate rs334558 polymorphism, promoter methylation status and CDH1 expression profile in breast cancer patients. Materials and methods: We collected peripheral blood samples from 102 breast cancer patients and 102 healthy subjects. The identification of rs334558 polymorphism was performed using PCR-RFLP, while methylation-specific PCR (MSP) and methylation-sensitive high-resolution melting (MS-HRM) were used to explore CDH1 methylation status; finally, CDH1 transcriptional expression profile was evaluated using RT-qPCR. Results: We found no association between rs334558 polymorphism and breast cancer. Aberrant promoter methylation profile was found in breast cancer patients and it was related with early cancer stages. CDH1 down-regulation was significantly associated with metastasis and promoter methylation. Conclusion: CDH1 alterations were associated with invasion and metastasis in breast cancer. Our results offer further evidence of CDH1 relevance in breast cancer development and progression.
Assuntos
Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Transcrição Gênica , Neoplasias da Mama/genética , Caderinas/genética , Regulação Neoplásica da Expressão Gênica , Polimorfismo de Nucleotídeo Único , Proteínas de Neoplasias/genética , Neoplasias da Mama/epidemiologia , DNA de Neoplasias/genética , DNA de Neoplasias/química , RNA Mensageiro/biossíntese , RNA Neoplásico/genética , Antígenos CD , Caderinas/biossíntese , Caderinas/fisiologia , Fatores de Risco , Regiões Promotoras Genéticas , História Reprodutiva , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/epidemiologia , Metilação de DNA , Predisposição Genética para Doença , Epigênese Genética , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/fisiologiaRESUMO
Summary Objective: our aim was to evaluate whether somatic mutations in five genes were associated with an early age at presentation of breast cancer (BC) or serous ovarian cancer (SOC). Methods: COSMIC database was searched for the five most frequent somatic mutations in BC and SOC. A systematic review of PubMed was performed. Young age for BC and SOC patients was set at ≤35 and ≤40 years, respectively. Age groups were also classified in <30years and every 10 years thereafter. Results: twenty six (1,980 patients, 111 younger) and 16 studies (598, 41 younger), were analyzed for BC and SOC, respectively. In BC, PIK3CA wild type tumor was associated with early onset, not confirmed in binary regression with estrogen receptor (ER) status. In HER2-negative tumors, there was increased frequency of PIK3CA somatic mutation in older age groups; in ER-positive tumors, there was a trend towards an increased frequency of PIK3CA somatic mutation in older age groups. TP53 somatic mutation was described in 20% of tumors from both younger and older patients; PTEN, CDH1 and GATA3 somatic mutation was investigated only in 16 patients and PTEN mutation was detected in one of them. In SOC, TP53 somatic mutation was rather common, detected in more than 50% of tumors, however, more frequently in older patients. Conclusion: frequency of somatic mutations in specific genes was not associated with early-onset breast cancer. Although very common in patients with serous ovarian cancer diagnosed at all ages, TP53 mutation was more frequently detected in older women.
Resumo Objetivo: avaliar se mutações somáticas em câncer de mama e seroso de ovário estão associados com pacientes jovens. Métodos: com base no COSMIC, foram selecionados os cinco genes mais frequentes mutados em câncer de mama e seroso de ovário. Em seguida, realizou-se uma revisão sistemática no PubMed. Pacientes jovens foram classificadas com ≤35 anos e ≤40 anos para câncer de mama e seroso de ovário, respectivamente. Classificaram-se também as pacientes em grupos etários de ≤30 anos, separados a cada 10 anos. Resultados: vinte e seis (1.980 pacientes, 111 jovens) e 16 estudos (598, 41 jovens) foram selecionados para câncer de mama e seroso de ovário, respectivamente. Em câncer de mama, pacientes jovens apresentaram baixa frequência de mutações somáticas em PIK3CA. Tumor HER2 negativo foi associado a mutações somáticas em PIK3CA no grupo etário mais avançado, e em tumores ER positivos foi observada uma tendência a essa associação. Mutações somáticas em TP53 foram observadas em 20% dos tumores, em ambos os grupos (≤35 anos vs. ≥35 anos). Mutações somáticas em PTEN, CDH1 e GATA3 foram analisadas em 16 pacientes e apenas uma apresentou mutação em PTEN. Em câncer seroso de ovário, mutações somáticas em TP53 foram detectadas em mais que 50% dos tumores; entretanto, foram mais frequentes em pacientes idosas. Conclusão: a frequência de mutações somáticas nos genes selecionados não foi associada com pacientes jovens. Embora muito comum em pacientes com câncer seroso de ovário, mutações somáticas em TP53 foram mais frequentes em pacientes mais velhas.
Assuntos
Feminino , Humanos , Adulto Jovem , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Mutação , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/genética , Fatores Etários , /genética , /genéticaRESUMO
La transición epitelial-mesenquimal es un proceso mediante el cual las células tumorales pierden sus marcadores epiteliales y facilita la migración a órganos distantes. En este proceso intervienen diversas proteínas de adhesión celular, tales como la cadherina E y la cadherina P. El presente estudio se realizó en 354 pacientes diagnosticadas de carcinoma ductal infiltrante de mama en seguimiento, en el Instituto de Oncología Dr. Miguel Pérez Carreño de Valencia, Venezuela. Se analizó la expresión de las dos moléculas por matrices de tejidos y se compararon los resultados obtenidos con las clases moleculares definidas por inmunohistoquímica, de acuerdo a la expresión de receptores de estrógeno (RE), receptores de progesterona (RP) y receptor del factor de crecimiento epidérmico humano 2 (HER2) y con la supervivencia global (SG). Con base a los resultados de RE, RP y HER2 se establecieron las clases moleculares, obteniendo los siguientes porcentajes: Luminal A 42,4%, Luminal B 20,3%, HER2 9% y triple negativo (TN) 28,2%. La expresión de cadherina E se observó conservada en la mayoría de los tumores de esta serie, 92,5% de los casos. Los tumores de fenotipo TN presentaron un porcentaje elevado (41,7%) con expresión ausente o reducida. La cadherina P se expresó en el 40,5% de los casos, y aunque expresada en todas las clases, la proporción fue significativamente mayor en los casos TN. No se apreció valor pronóstico significativo al analizar la SG a 5 años de las pacientes con tumores con ausencia o expresión reducida de cadherina E. La expresión de cadherina P presentó relación negativa con la SG.
The epithelial-mesenchymal transition is a process by which tumor cells lose their epithelial markers and migrate to distant organs. This process involves several cell adhesion proteins such as E-cadherin and P-cadherin. The present study was performed in 354 pacients diagnosed with breast infiltrating ductal carcinoma in the Oncology Institute Dr. Miguel Pérez Carreño, Valencia, Venezuela. The expression of 22 molecules was analyzed by tissue micro-arrays and the results were compared with the molecular clases established by immunohistochemistry, according to the expression of estrogen receptor (ER), progesterone (PR) and human epidermal growth factor receptor type 2 (HER2), and with the overall survival (OS). Based on the results of ER, PR and HER2 molecular classes according to the following percentages were established: Luminal A 42.4%, Luminal B 20.3%, 9% HER2 and 28.2% triple negative (TN). E-cadherin expression was observed conserved in most of the tumors of this series, 92.5% of cases. TN phenotype tumors showed a high percentage (41.7%) with absent or reduced expression. The P-cadherin was expressed in 40.5% of cases, although expressed in all classes; the proportion was significantly higher in cases TN. No significant prognostic value was observed when analyzing the overall five-year survival of patients with tumors with absent or reduced expression of E-cadherin. The P-cadherin expression had a negative relationship with the OS.
Assuntos
Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias da Mama/genética , Caderinas/genética , Carcinoma Ductal de Mama/genética , Prognóstico , Venezuela , Neoplasias da Mama/patologia , Imuno-Histoquímica , Receptores de Progesterona/genética , Receptores de Estrogênio/genética , Regulação Neoplásica da Expressão Gênica , Estudos Transversais , Taxa de Sobrevida , Estudos Retrospectivos , Carcinoma Ductal de Mama/patologia , Receptor ErbB-2/genética , Transição Epitelial-Mesenquimal/genéticaAssuntos
Adulto , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , /genética , Neoplasias da Mama Masculina/genética , Carcinoma Ductal de Mama/genética , Carcinoma Lobular/genética , Carcinoma Papilar/genética , Receptores Androgênicos/genética , Neoplasias da Mama Masculina/complicações , Neoplasias da Mama Masculina/epidemiologia , Carcinoma Ductal de Mama/epidemiologia , Carcinoma Lobular/etnologia , Carcinoma Papilar/epidemiologia , Egito/epidemiologia , Predisposição Genética para Doença , Cirrose Hepática/complicações , Marrocos/epidemiologia , Repetições de Trinucleotídeos/genéticaRESUMO
BACKGROUND: BRCA protein interacts with at least 13 different proteins that have been implicated with cancer susceptibility and loss of BRCA function is correlated to sensitivity to DNA crosslinking agents in preclinical models. RESULTS: BRCA2 methylation frequency was 44%, p53 Pro22 allele frequency was 32% and heterozygous frequency of Arg/Pro72 genotype was 60% which could be associated as risk factor for metastasis (p = 0.046 OR = 4.190). Regarding to polymorphism of codon 249 the frequency of Arg249 allele presented 82% which was considered not statistically significant. CONCLUSIONS: There was not statistical significance to BRCA2 promoter methylation with any parameters chosen. However, our findings suggest that patients who present heterozygous genotype at codon 72 of p53 gene may have a major susceptibility to any type of metastasis and this could serve as potential auxiliary biomarker for poor prognosis.
Assuntos
Feminino , Humanos , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Metilação de DNA/genética , Alelos , Brasil , Ilhas de CpG/genética , Genótipo , Mutação , Polimorfismo Genético , Reação em Cadeia da Polimerase/métodos , Regiões Promotoras Genéticas/genética , Fatores de Risco , Estatística como AssuntoRESUMO
O carcinoma ductal da mama é o tipo histológico mais freqüente, sendo que o in situ (CDIS) representa uma neoplasia com incidência crescente, devido aos métodos de detecção precoce de lesões mamárias não palpáveis. Essa neoplasia da mama inclui um grupo heterogêneo de tumores pré-invasivos, com potencial maligno distinto, que podem progredir rapidamente para a forma invasiva, ou não apresentarem evolução, após um longo período da doença. Um estudo prévio (CASTRO et al. 2008) aplicou o conceito de divergência molecular em grupos de lesões que mimetizam a progressão do câncer de mama [epitélio normal (EN), carcinoma ductal in situ (CDIS) puro, componente in situ de lesão que coexiste com invasão (CDIS-CDI) e do carcinoma ductal invasivo (CDI)], utilizando as metodologias de microdissecção a laser e cDNA microarray. O padrão de expressão gênica do grupo de células epiteliais tumorais do componente in situ do CDIS-CDI é semelhante ao grupo de células tumorais do CDI e diferente do grupo de células CDIS puro, cujos aspectos morfológicos são semelhantes ao componente in situ do CDIS-CDI. Isso sugeriu que as modificações moleculares das células do componente in situ do CDIS-CDI, já estejam presentes antes da manifestação morfológica de invasão e que os genes diferentemente expressos entre os dois grupos de células de lesões pré-invasivas, sejam potenciais preditores de risco de progressão do CDIS puro. Assim, nós avaliamos 28 genes das vias de sinalização WNT, PI3K e processo EMT, previamente selecionados do estudo anterior (CASTRO et al. 2008) através de RT-PCR quantitativo (RT-qPCR), em células tumorais capturadas de amostras congeladas do CDIS puro e do componente in situ do CDIS-CDI. Esse trabalho confirmou a diferença de expressão em células epiteliais entre os dois grupos de lesões pré-invasivas, em 14 (70%) de 20 genes avaliados, que apresentaram dados confiáveis nos ensaios de TLDA, sendo que 13 genes apresentaram maior expressão em CDIS...
Among breast tumors, ductal breast carcinoma is the most common histologic type. Ductal carcinoma in situ (DCIS) has increasing incidence, mainly due to early detection methods of non-palpable breast lesions. DCIS includes a heterogeneous group of pre-invasive tumors, with distinct malignant potential, which can either rapidly progress to the invasive form, or show no progression after a long period of surveillance. In a previous study from the group (CASTRO et al. 2008) based on the expression pattern of epithelial cells, using laser capture microdissection and cDNA microarray, the concept of molecular divergence was applied to groups of breast lesions which mimic the progression of breast cancer [cells from normal epithelium, cells from pure ductal carcinoma in situ (DCIS), cells from in situ component that coexists with invasive lesion (DCIS-IDC) and cells from invasive ductal carcinoma (IDC)]. The gene expression pattern of the cells from the in situ component of DCIS-IDC is more similar to the group of IDC tumor cells other than to the group of pure DCIS of cells, which presents higher similarity in terms of morphological features to the in situ component of DCIS-IDC. This suggests that the molecular changes of the cells from the in situ component of DCIS-IDC are already present before morphological manifestations of invasion and that the genes differentially expressed between the two groups of cells of pre-invasive lesions, are potential predictors of risk of progression of pure DCIS. Thus, we evaluated 28 previously selected genes of WNT signaling pathway, PI3K and EMT process (CASTRO et al. 2008) by quantitative RT-PCR (RT-qPCR) in tumor cells captured from in situ lesions of pure DCIS and DCIS-IDC from frozen samples. This work confirmed the difference in expression of epithelial cells between the two groups of preinvasive lesions, in 14 (70%) of the 20 genes evaluated, by reliable TLDA assays. Most genes (13 genes) showed higher expression in pure...
Assuntos
Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Ductal de Mama/genética , Imuno-Histoquímica , Perfilação da Expressão Gênica , Proteína Wnt1 , Biomarcadores TumoraisRESUMO
OBJECTIVE: To identify the prevalence of oestrogen receptor (ER) positivity, and determine the relationship of ER status with patient and tumour characteristics, in patients with breast cancer. SUBJECTS AND METHODS: A retrospective review was conducted regarding the prevalence and clinical significance of ER in patients with breast cancer at the University Hospital of the West Indies (UHWI). Oestrogen receptor status results of 243 patients treated at UHWI were collected for the period January 1, 2002 to December 31, 2009. One hundred and ninety-nine were available for review. RESULTS: Oestrogen receptor status was positive in 125 (63%) and negative in 74 (37%) patients. Mean age at diagnosis was 52.6 ± 13.0 years for the ER positive group and 58.5 ± 14.23 years for the ER negative group. Postmenopausal women accounted for 55.2% and 64.9% of the ER positive and negative groups, respectively. Mean BMI was 28.0 kg/m² and 29.6 kg/m² for the ER positive and negative groups, respectively. Menarche occurred mainly between ages 12 and 13 years for both groups. Mean age at 1st parity was 23.4 years for the ER positive and 21.4 years for the ER negative group with median parity of two for both groups. The most prevalent risk factors were oral contraceptive pill (OCP) use (24.3% for the ER positive group, 17.1% for the ER negative group), family history of breast cancer (12.0%; 13.4%) and previous smoking (8.4%; 6.9%). Tumour node metastasis (TNM) stage was Stage II in most cases (46%; 49%). Infiltrating ductal histology was most common (81.5%; 87.7%). Her 2/ neu status was negative for most patients (91.3%; 91.5%). Most patients were disease free (77.6%; 70.0%) after an average follow-up period of 3.5 years. More persons in the ER negative group had locoregional recurrence (8%) and metastases (22%). CONCLUSIONS: Oestrogen receptor positive cohort was more prevalent. The ER negative group was older (p = 0.003).
OBJETIVO: Identificar la prevalencia del receptor de la positividad de receptor de estrógeno (RE), y determinar la relación del estatus de RE con el paciente y las características del tumor, en las pacientes con cáncer de mama. SUJETOS Y MÉTODOS: Se realizó un estudio retrospectivo con respecto a la prevalencia e importancia clínica del RE en los pacientes con cáncer de mama en el Hospital Universitario de West Indies (UHWI). Se recogieron los resultados del estatus del receptor de estrógeno de 243 pacientes tratados en UHWI en el periodo del 1 de enero de 2002 al 31 de diciembre de 2009. Ciento noventa y nueve estuvieron disponibles para examen. RESULTADOS: El estatus del receptor de estrógeno fue positivo en 125 (63%) y negativo en 74 (37%) pacientes. La edad promedio al momento del diagnóstico fue 52.6 ± 13.0 años para el grupo de RE positivo y 58.5 ± 14.23 años para el RE grupo negativo. Las mujeres menopáusicas representaron el 55.2% y el 64.9% del RE de los grupos positivos y negativos respectivamente. El índice de masa corporal (IMC) promedio fue 28.0 kg/m2 y 29.6 kg/m2 para el RE de los grupos positivos y negativos respectivamente. La menarquia ocurrió principalmente entre las edades de 12 y 13 años para ambos grupos. La edad promedio en la primera paridad fue 23.4 años para el grupo de RE positivo y 21.4 años para el de RE negativo, siendo la paridad mediana igual a dos para ambos grupos. Los factores de riesgo de mayor preponderancia fueron el uso de anticonceptivos orales (ACO) (24. 3% para el grupo de RE positivo, 17.1% para el grupo RE negativo); historia familiar de cáncer de mama (12.0%; 13.4%); y hábito de fumar con anterioridad (8.4%; 6.9%). De acuerdo con la estadificación tumor-nódulo-metástasis (TNM), se trataba de la Etapa II en la mayor parte de los casos (46%; 49%). La histología ductal infiltrante fue la más común (81.5%; 87.7%). El estatus Her2/neu fue negativo para la mayoría de las pacientes (91.3%; 91.5%). La mayoría de las pacientes se hallaban libres de enfermedad (77.6%; 70.0%) después de un periodo promedio de seguimiento de 3.5 años. En el grupo de RE negativo había más personas con recurrencia locoregional (8%) y metástasis (22%). CONCLUSIONES: La cohorte positiva del receptor de estrógeno positiva fue más prevaleciente. El grupo negativo de RE fue de mayor edad (p = 0.003).
Assuntos
Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Pessoa de Meia-Idade , Adulto Jovem , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/metabolismo , Receptores de Estrogênio/metabolismo , Fatores Etários , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/secundário , Anticoncepcionais Orais , Jamaica , Menarca , Gradação de Tumores , Estadiamento de Neoplasias , Paridade , Pós-Menopausa/metabolismo , /metabolismo , Estudos Retrospectivos , FumarRESUMO
Em trabalho anterior realizado pelo nosso grupo, descrevemos que o gene NDRG4 se encontra silenciado em linhagens tumorais de mama devido a presença de metilação na sua região promotora. Neste trabalho, exploramos o papel do silenciamento do gene NDRG4 na tumorigênese da mama. Em um primeiro momento, investigamos a associação entre a presença de metilação na região promotora do gene NDRG4 em 61 amostras de tumores de mama e os dados clínico-patológicos das pacientes. Observamos uma associação estatisticamente significativa entre a presença de metilação do DNA na região promotora do gene NDRG4 e fatores de pior prognóstico, tais como: número de linfonodos positivos (p=0,025), níveis elevados da proteína p53 (p=0,014) e o tamanho do tumor (p=0,036); bem como com uma menor taxa de sobrevida livre de metástase em 10 anos (p=0,001). Em análise multivariada, a presença de metilação do DNA na região promotora do gene NDRG4 se mostrou um fator independente de prognóstico para sobrevida livre de mestástase (HR=5.5 e p=0.006). Paralelamente, realizamos o silenciamento do gene NDRG4 na linhagem de tumor de mama MCF7 utilizando a metodologia de shRNA. Variantes celulares, silenciadas para o gene NDRG4, apresentaram uma redução significativa na taxa de proliferação e na capacidade de formação de colônias isoladas e um aumento significativo na capacidade de migração. No entanto, não foram observadas diferenças significativas na capacidade de adesão e na susceptibilidade a taxanos dos clones silenciados
Assuntos
Humanos , Feminino , Carcinoma Ductal de Mama/genética , Expressão Gênica , Metilação de DNA , Neoplasias da MamaRESUMO
Objetivo Caracterizar epidemiológicamente el cáncer de mama y su evolución en la Región de Arica y Parinacota para el decenio 1997- 2007, Chile Método Se realizó un estudio descriptivo de tendencia. Se revisaron las historias clínicas de 306 casos pesquisados, consultantes del Policlínico de Oncología Mamaria del Hospital en Red Dr. Juan Noé Crevani. Se realizó un análisis descriptivo univariado de cada variable estudiada y se evaluó la tendencia de la incidencia y mortalidad de cáncer de mama. Resultados De los 306 casos estudiados durante el periodo, el 51,3 por ciento tuvo entre 46 y 65 años de edad, siendo el 13,9 por ciento de origen Aymara. El 70,2 por ciento de las pacientes eran menopáusicas, 98,4 por ciento sin tratamiento hormonal. El 12 por ciento refirió tener antecedentes familiares, de los cuales la hermana fue lo más frecuente. El 84,1 por ciento tuvo el diagnostico de carcinoma ductal infiltrante, un 32,8 por ciento de estos en etapa IIA. De todos los casos, el 31,6 por ciento presentó metástasis múltiple, con 74,7 por ciento en un rango de edad entre of 56 a 94 años. El análisis de la serie indica una tendencia creciente de nuevos casos y una moderada tendencia a la diminución de la tasa de mortalidad. Conclusiones La Región de Arica y Parinacota de Chile, muestra una tendencia creciente absoluta y relativa de nuevos casos de cáncer de mama durante el decenio estudiado. Por otra parte, la tasa mortalidad tendió a la disminución en el periodo. Ambos situaciones se explicarían en parte por el diagnóstico precoz y las políticas de salud implementados.
Objective Epidemiologically characterizing breast cancer in the Arica and Parinacota region in Chile and its evolution during 1997-2007. Method A descriptive, cross-sectional study was performed. All clinical histories for 306 cases of breast cancer were reviewed. All patients were detected through the Arica Juan Noé Crevani Hospital's Oncological Mammary Polyclinic from 1997 to 2007. A descriptive data analysis was made, followed by a tendency analysis. Results 51.3 percent of the 306 cases studied were aged 46 to 65 years, 13.9 percent being of Aymara ethnic origin. 70.2 percent of the women involved in the study were climacteric, 98.4 percent being without hormonal treatment. 12 percent referred to having a family background of cancer, the sister being the most frequently referred to relative. 84.1 percent had a histological diagnosis of infiltrating ductal carcinoma, stage IIA being the most frequently occurring one (32.8 percent). 31.6 percent presented multiple metastases, 74.7 percent of this group being aged 56 to 94. Time series analysis indicated an increasing incidence rate and decreasing mortality rate. Conclusions The Arica and Parinacota region of Chile presented an increasing tendency for new cases of breast cancer during the period being studied which was concentrated during the early stages of evolution. These findings could be explained by the early detection of breast cancer and the implementation of public health policy.
Assuntos
Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Mama/epidemiologia , Biópsia , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/epidemiologia , Carcinoma Ductal de Mama/genética , Carcinoma Lobular/epidemiologia , Carcinoma Lobular/genética , Chile/epidemiologia , Estudos Transversais , Etnicidade/estatística & dados numéricos , Terapia de Reposição Hormonal , Incidência , Menopausa , História Reprodutiva , Resultado do TratamentoRESUMO
Background: Proteins encoded by FAS, BCL-2 and TP53 genes are major regulators of cellular survival and apoptosis. Results of recent investigations show remarkable biological features of these factors, which propose their role in the course of cancer. Therefore, it is plausible to test whether transcripts of these genes could be detected in the peripheral blood cells of patients with breast cancer. Materials and Methods: Real-time polymerase chain reaction assay was performed to detect FAS, BCL-2, and TP53 gene transcripts in the peripheral blood samples of 50 women with histologically confirmed infiltrative ductal carcinoma of the breast. Gene expression of patients was compared with 40 healthy women without history of malignancies or autoimmune disorders. Results: The relative overexpression of BCL-2 in the blood cells from patients of early stages (I and II), nonmetastatic and low-grade tumors compared with healthy individuals, was shown by measuring the gene transcript. Similarly, 3-4-fold higher expression of FAS was found in those patients. The measurement of TP53 transcripts also showed higher levels of gene expression in patients compared with healthy controls. BCL-2 gene expression showed a significant correlation with FAS, while such a correlation was not observed between BCL-2 and TP53 . Conclusion: It seems tumor cells overexpress BCL-2 to inhibit apoptosis and guarantee their cell survival. As a physiologic response, FAS and TP53 could be upregulated to suppress tumors. However, these pathways at early stages of disease may be inadequate and cause progressive malignancy.
Assuntos
Receptor fas/sangue , Receptor fas/genética , Neoplasias da Mama/sangue , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/sangue , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/sangue , Proteínas Proto-Oncogênicas c-bcl-2/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição Gênica , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Proteína Supressora de Tumor p53/sangue , Proteína Supressora de Tumor p53/genéticaRESUMO
OBJECTIVE: To evaluate the distribution of molecular subtypes of breast tumors diagnosed in young Brazilian women and to analyze the frequency of loss of heterozygocity (LOH) in BRCA1 among different molecular subtypes of early-onset breast cancer. METHODS: Samples from 72 cases of invasive breast carcinoma diagnosed in women aged between 19 and 40 years were evaluated using an immunohistochemical panel of biomarkers. Three intragenic BRCA1 locus microsatellites, D17S1322, D17S1323, and D17S855, were PCR amplified from matched normal (lymphocyte) and tumor DNAs for (LOH) analysis. RESULTS: We found 13 cases (18 percent) that had an immunohistochemical profile consistent with being basal-like. Forty cases (55 percent) were luminal A type; 11 percent (8 cases) were luminal B type, 13 percent (9 cases) were HER2-overexpressing tumors and two cases were ER-/HER2- carcinomas lacking basal marker expression. Four of the 16 informative cases at D17S1322, one of the four informative cases at D17S855, and none of the five informative cases at D17S1323 displayed LOH (four basal-like and one Luminal A). Microsatellite instability (MSI) at D17S855 and D17S1322 was found in two cases (one a basal-like and one Luminal A). CONCLUSION: In our study, basal-like tumor was the second most frequent molecular type among young Brazilian women and was only observed in women diagnosed under the age of 35 years. There was no significant difference of LOH at BRCA1 locus rates between basal-like breast tumors and not-basal-like breast tumors (p=0.62). LOH in BRCA1 and MSI in these breast cancers were not frequent but may indicate a small group of breast cancers with a specific molecular makeup.
OBJETIVO: Avaliar a distribuição dos subtipos moleculares dos tumores de mama diagnosticados em mulheres brasileiras jovens e determinar a frequência de perda de heterozigose (LOH) no gene BRCA1 entre os diferentes subtipos moleculares de tumores. MÉTODOS: Setenta e dois casos de carcinoma invasivo de mama diagnosticados em mulheres entre 19 e 40 anos de idade foram classificados de acordo com o subtipo molecular utilizando um painel imunoistoquímico e para a análise de LOH foram utilizados três marcadores intragênicos para o gene BRCA1 (D17S1322, D17S855, D17S1323). RESULTADOS: Treze casos (18 por cento) apresentaram perfil imunoistoquímico compatível com carcinoma do tipo basal (basal-like tumor). Quarenta casos (55 por cento) foram classificados como tumores do tipo luminal A; 11 por cento (oito casos) do tipo luminal B, 13 por cento (nove casos) corresponderam a tumores com superexpressão de HER2 (HER2-overexpressing tumors) e dois casos corresponderam a carcinomas ER/HER2 negativos sem expressão de marcadores basais. LOH foi detectada em quatro dos 16 casos informativos para o marcador D17S1322 e em um dos quatro casos informativos para D17S855. Instabilidade de microssatélites (MSI) foi observada em dois casos, um do tipo basalóide e um do tipo luminal A. CONCLUSÃO: Carcinomas do tipo "basal-like" corresponderam ao segundo subtipo molecular mais frequente entre os tumores de mama diagnosticados neste grupo de mulheres e foram restritos às mulheres com idade inferior a 35 anos. Não houve diferença significativa na frequência de LOH no gene BRCA1 entre os subtipos moleculares (p= 0,62). A frequência de LOH e de instabilidade de microssatélite em BRCA1 foi baixa neste grupo de pacientes, porém podem indicar um pequeno grupo de cânceres de mama com características moleculares específicas distintas.
Assuntos
Adulto , Feminino , Humanos , Adulto Jovem , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Genes BRCA1 , Perda de Heterozigosidade/genética , /genética , Brasil , Distribuição de Qui-Quadrado , Regulação Neoplásica da Expressão Gênica , Instabilidade de Microssatélites , Neoplasia de Células Basais/genética , Biomarcadores Tumorais/sangueRESUMO
Some mammary carcinomas are uncommon and have poor prognosis. Pleomorphic lobular carcinoma of the breast is one of these types. This variant hinders its correct identification and differentiation from duct carcinoma, particularly the higher histological grade of the latter. E-cadherin-beta catenin complex is a powerful tool for this differentiation. E-cadherin is a transmembrane glycoprotein mediates epithelial cell-to-cell adhesion. Loss of E-cadherin results in disruption of the cellular clusters. Sometimes invasive duct carcinoma demonstrated an invasive lobular growth pattern. Additionally, some variants of invasive lobular carcinoma particularly pleomorphic and tubulolobular types are difficult to be differentiated from invasive duct carcinoma in particular when the latter demonstrated higher histological grades. As these types are differening in their clinicopathological characters, treatment strategy, and prognostic behaviors, so, the differentiation between them is very important. E-cadherin expression can solve this diagnostic dilemma as it expressed strongly in most invasive duct carcinoma and lacked in many lobular neoplasia. The aim of this study is evaluate E-cadherin-beta-catenin expression in invasive duct carcinoma, invasive classic lobular carcinoma, and pleomorphic lobular carcinoma. As sometimes the histologic differentiation between advanced types of invasive duct and lobular carcinomas is so difficult, it is important for this differentiation to be made. In these equivocal cases, Immunohistochemical detection of E-cadherin-beta catenin expression is of useful diagnostic aid. Additionally, to demonstrate the clinicopathological characters of pleomorphic lobular carcinoma. Antibodies to E-cadherin-beta-catenin, and HER-2 neu were used immunohistochemically in 55 cases of mammary carcinomas. These cases included 35 cases [63.6%] invasive duct carcinoma, 6 cases [10.9%] invasive duct carcinoma with lobular features, 9 cases [16.4%] classic invasive lobular carcinoma, 4 cases [7.3%] pleomorphic lobular carcinoma, and one case [1.8%] was tubulolobular carcinoma. As well as antibody against high molecular weight cytokeratin [HMWCK] was included in this study. This series study revealed strong membranous immunostaining for E-cadherin in 32 cases [91.4%] of invasive duct carcinoma. While the remaining 3 cases [8.6%] of were negative. Additionally, all the included 6 cases of invasive duct carcinoma with lobular features were positive for E-cadherin membranous immunostaining. As well as all cases of invasive duct carcinoma showed membranous immunostaining for beta-catenin immunoexpression. In the opposite direction all cases of classic invasive, pleomorphic lobularand the included case of tubulolobular carcinomas were lacked any membranous immunostaining for E-cadherin and beta-catenin immunoexpression. Among invasive duct carcinoma 10 cases [28.6%] revealed HER-2 neu positive immunostaining, while the remaining 25 cases [71.4%] of them lacked HER-2 new immunoreactivity. Among the invasive duct carcinoma with lobular features 2 out of the 6 cases revealed HER-2 neu positive membranous immunoreactivity. In the other hand HER-2 neu reactivity was detected in one case [11.1%] of classic invasive lobular carcinoma, while the remaining 8 cases [87.9%] of them lacked HER-2 neu immunostaining. Two cases [50%] of pleomorphic lobular carcinoma were positive for HER-2 neu immunoexpression, while the other 2 cases [50%] were negative. The included single tubulolobular carcinoma case was negative for HER-2 neu immunoreactivity. Our study demonstrates a strong positive E-cadherin-beta-catenin immunoreactivity in the majority of invasive duct carcinoma. The classic invasive and pleomorphic lobular carcinomas were negative for E-cadherin-beta-catenin immunoexpression. So, E-cadherin-beta-catenin complex is very important immunohistochemical marker for the differentiation between the two common and important types of mammary carcinomas
Assuntos
Humanos , Feminino , Carcinoma Ductal de Mama/genética , Caderinas , Imuno-Histoquímica , beta CateninaRESUMO
Epithelial intercellular cohesion, mainly mediated by E-cadherin (CDH1) expression and function, may be deregulated during cancer cell invasion of adjacent tissues and lymphatic and vascular channels. CDH1 expression is down-modulated in invasive lobular breast carcinomas but its regulation in invasive ductal carcinomas (IDC) is less clear. CDH1 expression is repressed by transcription factors such as Snail (SNAI1) and its product is degraded after Hakai ubiquitination. We compared CDH1, SNAI1 and HAKAI mRNA expression in IDC and paired adjacent normal breast tissue and evaluated its relation with node metastasis and circulating tumor cells. Matched tumor/peritumoral and blood samples were collected from 30 patients with early IDC. Epithelial cells from each compartment (tumor/peritumoral) were recovered by an immunomagnetic method and gene expression was determined by real time RT-PCR. There were no differences in CDH1, SNAI1 and HAKAI mRNA expression between tumor and corresponding peritumoral samples and no differential tumoral gene expression according to nodal involvement. Another 30 patients with a long-term follow-up (at least 5 years) and a differential prognosis (good or poor, as defined by breast cancer death) had E-cadherin and Snail protein detected by immunohistochemistry in tumor samples. In this group, E-cadherin-positive expression, but not Snail, may be associated with a better prognosis. This is the first report simultaneously analyzing CDH1, SNAI1 and HAKAI mRNA expression in matched tumor and peritumoral samples from patients with IDC. However, no clear pattern of their expression could distinguish the invasive tumor compartment from its adjacent normal tissue.
Assuntos
Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias da Mama/metabolismo , Caderinas/metabolismo , Carcinoma Ductal de Mama/metabolismo , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Caderinas/genética , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patologia , Células Epiteliais/química , Regulação Neoplásica da Expressão Gênica , Imuno-Histoquímica , Metástase Linfática , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Ubiquitina-Proteína Ligases/genéticaRESUMO
Paciente de género femenino de 51 años que en una revisión de rutina se observó lesión sospechosa de mama derecha, BIRADS IVa. Patología reportó cáncer ductal infiltrante moderadamente diferenciado con dos focos de carcinoma invasor separados de 2 y 1 mm, receptores de estrógeno y progesterona positivos. El cáncer de mama familiar abarca entre el 5 por ciento al 10 por ciento de cáncer de mama de la población en general. Los genes involucrados en este padecimiento son: BRCA1 en 20 por ciento, BRCA 2 en 20 por ciento, CHEK2 en 5 por ciento, TP 53 en 1 por ciento, sin embargo, en más del 50 por ciento de los casos se desconoce en gen asociado. El BRCA1 es un gen localizado en el cromosoma 17q21, supresor de tumor, involucrado en la regulación del ciclo celular, reparación del ADN dañado, mantenimiento de la estabilidad genómica y regulación de la transcripción. Existen indicaciones precisas para la búsqueda intencionada del gen BRCA en pacientes con historia familiar o personal de cßncer de mama y ovario.
51 year old female found on check up a suspicious lesion in right breast, BIRADS IVa. Pathology reported a ductal infiltrative moderately differentiated cancer with two separate carcinomas of 2 and 1 mm each, progesterone and estrogen receptors. Familiar breast cancer is calculated to be about 5-10 percent of all breast cancers. The genes involved are: BCRA1 in 20 percent, BRCA2 in 20 percent, CHEK2 in 5 percent, TP 53 in 1 percent, although more than 50 percent of cases are not associated with a gen. BRCA1 is a gene in chromosome 17q21, tumor suppressor, involved in the regulation of the cellular cycle, repair of damaged DNA, maintenance of genomic stability and regulation of transcription. Specific indications are in use for BCRA gene scouting in women with family or personal history of breast or ovary cancer.
Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Carcinoma Ductal de Mama/genética , Genes BRCA1 , Predisposição Genética para Doença , Neoplasias da Mama/genética , MutaçãoRESUMO
Background : In invasive ductal carcinoma (IDC), many antiapoptotic and proapoptotic genes regulate disease outcome. Hormone receptor-mediated mechanisms have also been shown to prevent apoptosis. Therefore, relations between hormone receptor status and other molecular markers need further examination. Aims : In the present study, we analyzed the expression of apoptosis-regulating genes, viz., Survivin and mutant p53, in benign breast disease (fibroadenoma) and IDC patients. Results were then correlated with hormone receptor status of the patients. Material and Methods : Paraffin-embedded tissue samples from 63 untreated female patients with IDC and 32 female patients with fibroadenoma were used. Expression of Survivin and mutant p53 was evaluated using immunohistochemical staining method. Statistical Analysis : Fisher exact test and nonparametric correlation test (Spearman rank correlation test) were performed. Results : In fibroadenoma, 53% of patients expressed Survivin and 13% of patients expressed p53 protein. Statistically significant increase in Survivin and p53 protein expression was observed in carcinoma cases. Survivin expression correlated negatively with progesterone receptor (PR) status, but its expression was independent of estrogen receptor (ER) status. p53 expression showed negative correlation with both ER and PR status. Conclusions : Increased expression of Survivin and p53 in IDC patients and correlation with hormone receptors suggest that Survivin and p53 along with hormone receptors status are likely to contribute significantly to apoptosis resistance and may serve as therapeutic target that could increase the effectiveness of conventional breast cancer therapy.
Assuntos
Adulto , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/patologia , Feminino , Fibroadenoma/genética , Fibroadenoma/imunologia , Fibroadenoma/patologia , Humanos , Imuno-Histoquímica , Índia , Proteínas Inibidoras de Apoptose/genética , Pessoa de Meia-Idade , Prognóstico , Receptores de Estrogênio/fisiologia , Receptores de Progesterona/fisiologia , Estudos Retrospectivos , Estatística como Assunto , Estatísticas não Paramétricas , Biomarcadores Tumorais , Proteína Supressora de Tumor p53/genética , Adulto JovemRESUMO
Background: The product of Wilms' tumor suppressor gene (WT1), a nuclear transcription factor, regulates the expression of the insulin-like growth factor (IGF) and transforming growth factor (TGF) systems, both of which are implicated in breast tumorigenesis and are known to facilitate angiogenesis. In the present study, WT1 allelic integrity was examined by Loss of Heterozygosity (LOH) studies in infiltrating breast carcinoma (n=60), ductal carcinoma in situ (DCIS) (n=10) and benign breast disease (n=5) patients, to determine its possible association with tumor progression. Methods: LOH at the WT1 locus (11p13) as determined by PCR-RFLP for Hinf1 restriction site and was subsequently examined for its association with intratumoral expression of various growth factors i.e. TGF-β1, IGF-II, IGF-1R and angiogenesis (VEGF and Intratumoral micro-vessel density) in breast carcinoma. Results: Six of 22 (27.2%) genetically heterozygous of infiltrating breast carcinoma and 1 of 4 DCIS cases showed loss of one allele at WT1 locus. Histologically, the tumors with LOH at WT1 were Intraductal carcinoma (IDC) and were of grade II and III. There was no correlation in the appearance of LOH at WT1 locus with age, tumor stage, menopausal status, chemotherapy status and lymph node metastasis. The expression of factor IGF-II and its receptor, IGF-1R was significantly higher in carcinoma having LOH at WT1 locus. A positive correlation was observed between the TGF-β1, VEGF expression and IMD scores in infiltrating carcinoma. Conclusions: The current study indicates that the high frequency of loss of allelic integrity at Wilms' tumor suppressor gene-1 locus in high-graded breast tumors is associated with aggressiveness of the tumor.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma in Situ/genética , Carcinoma in Situ/patologia , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patologia , Genes do Tumor de Wilms , Humanos , Fator de Crescimento Insulin-Like II/biossíntese , Perda de Heterozigosidade , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Receptor IGF Tipo 1/biossíntese , Fator de Crescimento Transformador beta1/biossíntese , Fator A de Crescimento do Endotélio Vascular/biossínteseRESUMO
Objective: To evaluate the expression of c-kit in breast invasive ductal carcinomas (IDC) and metastasis to lymph nodes considering epithelial and stromal components separately and correlate this variable to others clinical, pathological and biological markers (EGFR, Her-2, ER, PR, Ki-67 and p53 expression). Methods: We analysed 80 IDC, stage T2-T4 Nx Mx, in TMA of epithelial, stromal component and lymph nodes. Statistical analysis considered significant a p value < 5%. Results: c-kit expression was founded in 9 cases in epithelial component (11.3%) and in 10 cases (12.5%) of stromal component. The 43 samples of lymph nodes metastasis were negative. EGFR and Her-2 were predominantly negative, both in epithelial (77.5% and 73.75%, respectively), as stromal (97.5% and 95.0%) components and metastasis to lymph nodes (83.7% and 62.8%). While ER, PR, Ki-67 and p53 were positive in 49 (61.0%), 40 (53.0%), 67 (83.75%) and 59 cases (73.75%) in the epithelial component. Stromal cells have proved negatives. c-kit epithelial expression correlated to presence of in situ component (p = 0.044) and stromal c-kit expression correlated to presence of necrosis (p = 0.002). There was no association between c-kit expression and staging and biological markers. Transformed epithelial cells at me lymph nodes metastasis stained for ER, PR, Ki-67 and p53 in 27 (62.8%), 16 (37.5%), 41 (95.0%) and 28 cases (65.1%), respectively. Conclusions: The expression of c-kit is mostly negative in primary IDC both in the epithelial and stromal component, as well as in lymph node metastasis. The lack of correlation between c-kit and others tyrosine kinase proteins suggest that they are independently regulated. Metastasis for Iymph nodes were not c-kit positive and further studies of mutations of c-kit and his family, correlate with other prognostic factors and survival required to reveal the exact mechanism of action of this molecule in breast cancer.
Objetivo: Avaliar a expressão de c-kit em células epiteliais, estromais e metástases para linfonodos de carcinomas ductais mamários invasivos (CDI) e correlacionar essa variável com os outros marcadores clínicos, patológicos e biológicos (EGFR, HER-2, RE, RP, Ki-67 e p53). Métodos: Analisaram-se 80 CDI, estádios T2-T4 Nx Mx, em TMA de componente epitelial, estromal e linfonodos. O valor de p < 5% foi considerado significante. Resultados: A expressão de c-kit foi encontrada em 9 casos no componente epitelial (11,3%) e em 10 casos (12,5%) do componente estromal. As 43 amostras de metástases para linfonodos foram negativas. EGFR e Her-2 foram predominantemente negativos, tanto em epitélio (77,5% e 73,75%, respectivamente), como estroma (97,5% e 95,0%) e metástases para linfonodos (83,7% e 62,8%), enquanto RE, RP, Ki-67 e p53 foram positivos em 49 (61,0%), 40 (53,0%), 67 (83,75%) e 59 casos (73,75%) no componente epitelial. Células do estroma se mostraram negativas. A expressão de c-kit epitelial correlacionou-se com a presença do componente in situ (p = 0,044) e a expressão de c-kit no estroma se associou com a presença de necrose (p = 0,002). Não houve associação entre a expressão de c-kit com estadiamento e marcadores biológicos. Células epiteliais transformadas de metástases para linfonodos coraram para RE, RP, Ki-67 e p53 em 27 (62,8%), 16 (37,5%),41 (95,0%) e 28 casos (65,1%), respectivamente. Conclusões: A expressão de c-kit é majoritariamente negativa em CDI primário tanto no componente epitelial quanto no estromal, assim como em metástases linfonodais. A falta de correlação entre o c-kit e outras proteínas tirosina quinases sugere que elas sejam reguladas de forma independente. Metástases para linfonodos não foram positivas para c-kit, e estudos posteriores de mutações do c-kit e sua família, correlacionando com outros fatores prognósticos e sobrevida, são necessários para revelar o exato mecanismo de ação dessa molécula no câncer de mama.
Assuntos
Humanos , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patologia , Células Epiteliais/patologia , Células Estromais/patologia , Imuno-Histoquímica , Biomarcadores/metabolismo , Proteínas Proto-Oncogênicas c-kit/biossíntese , Estadiamento de Neoplasias , Neoplasias da Mama/patologiaRESUMO
Objetivos: Analisar características anatomopatológicas e perfil imuno-histoquímico dos carcinomas de mama em mulheres até os 35 anos. Método: Estudo retrospectivo com análise de casos recebidos no período de 1997 a 2007. Foram identificados 909 (6,6%) casos de jovens, dos quais 314 possuíam blocos de parafina disponíveis. Foi selecionado um grupo controle de 81 pacientes acima de 60 anos. Todos os casos foram revisados quanto a características anatomopatológicas. A pesquisa imuno-histoquímica de RE, RP e HER2 foi realizada em 291 casos de mulheres jovens e em 74 acima de 60 anos. Os tumores foram categorizados como luminal (RE e/ou RP positivo), HER2 (RE e RP negativos e HER2 positivo) e triplo-negativo (RE, RP e HER2 negativos). Resultados: O tipo histológico ductal invasivo foi o mais frequente nos dois grupos (95,2% em jovens e 83,90% acima de 60 anos). A frequência do tipo lobular foi menor no grupo jovem (2,5% x 12,3%), embora o subtipo pleomórfico tenha sido mais frequente. Pacientes jovens apresentaram mais frequentemente tumores de alto grau (41,7% x 28,4%) e tendência a tumores circunscritos (8,2% x 7,4%) e com necrose (23,2% x 16,0%). O perfil luminal foi mais frequente nos dois grupos, embora com proporção menor nas jovens (64,9% x 81,1%). Estas apresentaram maior frequência do perfil triplo-negativo (27,1% x 17,6%), mais superexpressão de HER2 (16,5% x 5,4%), e maior frequência do perfil HER2 puro (7,9% x 1,3%). Conclusões: Os resultados apontam para diferenças intrínsecas nos carcinomas em jovens, caracterizadas por perfis morfológico e imuno-histoquímico mais agressivos.
Aims: To analyse pathological features and immunohistochemical profile of breast carcinomas in women 35 years or less. Methods: Retrospective study with analysis of the cases received from 1997 to 2007. We identified 909 (6.6%) cases of breast cancer in young women, 314 of them with available paraffin blocks. A control group of 81 patients above age of 60 was selected. AlI the cases were revised regarding histological features. The immunohistochemical detection of ER, PR and HER2 was carried on 291 cases of young women and 74 in olders. The tumors were categorized as luminal (positive ER and/or PR), HER2 (negative ER and RP, and positive HER2), and triple-negative (negative ER, PR and HER2). Results: The ductal histological type was the most frequent one in the two groups (95.2% in young and 83.9% above 60 years). Infiltrative lobular carcinoma was less frequent in the young group (2.5% x12.3%), although the pleomorphic subtype was more frequent. Young women more often presented with high grade tumors (41.7% x 28.4%) and showed a trend to more circumscribed tumors (8.2% x 7.4%) and necrosis (23.2% x 16.0%). The luminal profile was more frequent in the two groups, although with lower frequency among younger (64.9% x 81.1%). These presented more triple-negative profile (27.1% x 17.6%), more overexpression 01 HER2 (16.5% x 5.4%), as well as the molecular profile HER2 (7.9% x 1.3%). Conclusions: The results point to intrinsic differences in the tumors arising in young women characterized by more aggressive morphological and immunohistochemical profiles.
Assuntos
Humanos , Feminino , Adulto , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Perfilação da Expressão Gênica , Imuno-Histoquímica , Estudos RetrospectivosRESUMO
O câncer de mama está entre as neoplasias de maior incidência e é responsável pela alta taxa de mortalidade entre as mulheres no mundo todo. O carcinoma ductal é o tipo histológico mais freqüente. O carcinoma ductalin situ (DCIS) inclui um grupo de tumores de mama pré-invasivos com potencial maligno distinto, podendo progredir rapidamente para carcinoma invasivo ou não apresentar evolução durante um longo período da doença. ... Neste estudo foram analisados 40 casos de mama, sendo 5 amostras de tecido de mamário não neoplásico(N), 16 casos de amostras pareadas de carcinoma ductal (in situ e invasivo), 5 DCIS puro, 9 DCIS coexistindo com o componente invasor (DCIS/IDC) e 5 carcinomas ductais invasivos (IDC). .... Dois delineamentos experimentais foram usados: comparação entre lesões in situ e invasivo da mesma amostra (DCIS e IDC); e comparação de grupos de lesões que mimetizam a progressão de câncer ductal de mama, utilizando amostras independentes [células epiteliais de mama capturadas de amostra não neoplásica (N), células tumorais capturadas das lesões: DCIS puro, DCIS/IDC e IDC]. ... Na comparação entre as 3 lesões (DCIS puro, DCIS/IDC e IDC), o DCIS puro mostrou maior divergência molecular, contradizendo os aspectos morfológicos. ... Esse resultado confirmou que o padrão de expressão entre essas lesões é semelhante mesmo avaliando genes sabidamente envolvidos no processo. ... Assim, baseado nos dados desse estudo, demonstramos que as células do carcinoma ductal in situ que coexistem com as células do carcinoma invasivo apresentam alterações moleculares antes da modificação morfológica da lesão, e isso pode ser explorado para se identificar genes alterados que possam predizer a capacidade de invasão. Além disso, esse estudo identificou vários genes candidatos a marcadores moleculares de prognóstico e também preditivos do risco de progressão de doença não invasiva.
Breast carcinoma is one of the most incidence neoplasias and is responsible for a high death-rate among women worldwide. The ductal carcinoma is the most frequent histological type. Ductal carcinoma in situ (DCIS) includes a group of preinvasive breast tumors with distinct malignant potentials. DCIS can have different outcomes, progressing rapidly to invasive cancer or slowly changing over a long period of the disease. Lately, one of the most challenges in molecular research in this field is to identify genes able to predict the risk of progression to invasive disease and prognostic marker. In this study were used 40 breast cases, being 5 non-neoplasic mammary tissues samples (N), 16 matched pairs of ductal carcinoma (in situ and invasive), 5 pure DCIS, 9 DCIS coexisting with invasive ductal carcinoma (DCIS/IDC) e 5 IDC. The RNA from epithelium cells laser capture microdissected were amplified and hybridized using reference design with dye swap in two distinct customized cDNA microarrays platforms. One containing 4.608 cDNA that represent human genes (4.8K) and other containing 390 genes belonging to WNT, PI3K signaling pathways and EMT process (Epithelial-mesenchymal transition). Two designing assays were used: comparisons between lesions in situ and invasive from the same patient (DCIS e IDC) and comparison among lesion groups that mimics the progression of breast ductal carcinoma using independent samples (breast epithelium cells microdissected of non-neoplasic tissues (N), tumoral cells microdissected of lesions: DCIS puro, DCIS/IDC e IDC. In the 4.8k platform, 16 matched-pair samples were used to compare the tumor cells expression profile of DCIS and IDC from the same patient. It was identified 33 candidates differentially expressed (t de Student pairwise - Fold >â1,5⥠e pvalue<0,01), being candidates' genes to be involved in transition from DCIS to IDC. To 4 (LUM, RDH-E2, CXCL13 e POSTN) of 8 selected genes was confirmed differential expression through quantitative RT-PCR (qRT-PCR). Two genes (LUM and CRABP2) over expressed in IDC were selected to verify association with others molecular markers and/or clinicopathological parameters through Tissue Microarray. The LUM protein expression showed positive association with CKs 5/6, CK 14, CK8 e 18 and HER2/neu positive, while CRABP2 showed positive association with ER, PR, CK8, CK18, luminal A, p53 and negatively with CK14. Seeking to characterize molecular aspects of ductal carcinoma in situ of the breast progression, the general gene expression profile among 4 groups that mimics the progression was analyzed (N, DCIS pure, CIS/IDC e IDC) performing ANOVA test (pFDR<0,01) and followed by Tukey´s test, being characterized as most diverge the N group, as expected. The comparison among the 3 lesions (DCIS pure, DCIS/IDC e IDC), the pure DCIS showed the most molecular divergence, contradicting the morphological aspects. To identify genes able to predict the potential risk of invasion of DCIS, it was compared the expression profile of two morphologically identical lesions (DCIS pure e DCIS/IDC), identifying 147 genes (ANOVA - Fold >â2⥠e pFDR<0,01). Hierarchical cluster based on expression profile of those genes could segregate the samples into two distinct groups in which 100% of non-neoplasic samples and 60% of pure DCIS remained in the same group and discriminated from DCIS/IDC (100%). Five (C16orf5, SULF-1, LOX, GOSR2 and TXNL2) candidates were confirmed through qRT-PCR as predict markers of DCIS progression. To assess the functional aspects of invasion process, it was used a platform containing genes belonging to WNT, PI3K signaling pathways and EMT process. The same experimental designing was used for 10 matched-pair, resulting in 32 differentially expressed genes between DCIS e IDC (t de Student pairwise - pvalue <0,05). This result confirmed that expression profile between the lesions is similar even assessing genes involved in this process. Between pure DCIS and DCIS/IDC were identified 15 differentially expressed genes (Wilcoxon p<0,05) whose expression profile could segregate the samples in the same way as for the 147 genes. Triple classifiers were built seeking to segregate the DCIS pure and DCIS/IDC samples. One gene triple belonged to each signaling pathways, WNT (CSNK1A1L, LRP3 and SDC2), PI3K (PLCG2, INPP1 and DGKA) and EMT process (HDGF, CDH13 e TWIST1) were able to segregate the samples being predictor candidates of DCIS progression. Hence, based on this study data, we showed that ductal carcinoma in situ coexisting with invasive ductal carcinoma presents molecular alteration before lesion morphological modifications, and this may be exploited to identify altered genes able to predict invasion capacity. Furthermore, this study identified many candidate genes to molecular markers for outcome and also predicting the risk of noninvasive disease progression.