Asunto(s)
Neoplasias Hepáticas/complicaciones , Linfoma de Células B de la Zona Marginal/complicaciones , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Anciano , Proteína de Unión a CREB/genética , Causalidad , Mutación del Sistema de Lectura , Gastritis/complicaciones , Infecciones por Helicobacter/complicaciones , Helicobacter pylori/aislamiento & purificación , Humanos , Inflamación , Neoplasias Hepáticas/genética , Linfoma de Células B de la Zona Marginal/genética , Masculino , Síndrome Metabólico/complicaciones , Proteínas de Neoplasias/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Mutación Puntual , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genéticaRESUMEN
BACKGROUND: CD44 and aldehyde dehydrogenase 1 (ALDH1) has been reputed to be cancer stem cell (CSC) markers in breast cancer. Yet, the clinicopathologic and prognostic significance of these markers remain unclear. In this study, we have investigated the expression of these markers and their relation with conventional clinicopathologic tumor characteristic including molecular subtype. METHODS: CD44 and ALDH1 expression were investigated by immunohistochemistry in a series of 157 formalin-fixed paraffin-embedded breast cancer tissues. RESULTS: Overall, CD44 and ALDH1 are, respectively, detected in 33% (52 of 157) and 7% (10 of 157) of breast cancer cases. We also observed that CD44 expression was associated with histological grade (p = 0.005). For ALDH1, we found that its expression is more frequent with elderly women (> 50 years, p = 0.03). The investigation of relationship between the stem cell phenotype and breast cancer molecular subtype, revealed that CD44 and ALDH1 expression was more frequent in basal-like tumors (p = 0.005). Among the two cancer stem cell markers tested, ALDH1 showed a strong association with the basal marker EGFR (p = 0.05). CONCLUSIONS: These findings suggest that CD44 and ALDH1 play a role in the clinical behavior in breast cancer and might be interesting biomarkers and therapeutic targets.
Asunto(s)
Neoplasias de la Mama/patología , Receptores de Hialuranos/análisis , Isoenzimas/análisis , Células Madre Neoplásicas/química , Retinal-Deshidrogenasa/análisis , Adulto , Anciano , Anciano de 80 o más Años , Familia de Aldehído Deshidrogenasa 1 , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/química , Femenino , Humanos , Receptores de Hialuranos/fisiología , Isoenzimas/fisiología , Persona de Mediana Edad , Retinal-Deshidrogenasa/fisiologíaRESUMEN
BACKGROUND: Previous investigations have indicated that CD10 is associated with biological aggressivity in human cancers, but the use of this marker for diagnosis and prognosis is more complex. The aim of this study was to evaluate the expression of CD10 in breast cancer and its association with the clinicopathological features. In addition, we investigated whether a relationship exists between CD10 expression and cancer stem cells. METHODS: CD10 expression was examined by the immunohistochemistry in a series of 133 invasive breast carcinoma cases. Results were correlated to several clinicopathological parameters. Cancer stem cell phenotype was assessed by the immunohistochemical analysis of CD44 and ALDH1. RESULTS: Significant CD10 expression was found in the fusiform stromal cells in 19.5% of the cases and in the neoplastic cells in 7% of the cases. The stromal CD10 positivity was more frequently found in tumors with lymph node metastasis (p = 0.01) and a high histological grade (p = 0.01). However, CD10 expression by the neoplastic cells correlates with a high histological grade (p = 0.03) and the absence of estrogen (p = 0.002) as well as progesterone (p = 0.001) receptor expression. We also found that CD10 expression by the stromal cells, but not by the neoplastic cells, correlates significantly with the expression of cancer stem cell markers (CD44+/ALDH1+) (p = 0.002). CONCLUSION: These findings support the role of the stromal CD10 expression in breast cancer progression and dissemination, and suggest a relationship with cancer stem cells.
Asunto(s)
Neoplasias de la Mama/genética , Células Madre Neoplásicas/patología , Neprilisina/genética , Pronóstico , Adulto , Anciano , Familia de Aldehído Deshidrogenasa 1 , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Receptores de Hialuranos/genética , Isoenzimas/genética , Persona de Mediana Edad , Células Madre Neoplásicas/metabolismo , Retinal-Deshidrogenasa/genética , Células del Estroma/metabolismo , Células del Estroma/patologíaRESUMEN
MicroRNAs (miRNAs) are small non-coding RNAs composed of 18-25 nucleotides that can post-transcriptionally regulate gene expression and have key regulatory roles in cancer, acting as both oncogenes and tumor suppressors. About 1000 genes in humans encode miRNAs, which account for approximately 3% of the human genome, and up to 30% of human protein coding genes may be regulated by miRNAs. The objective of this article is to evaluate the expression profile of four miRNAs previously implicated in triple negative breast cancer: miR-10b, miR-26a, miR-146a and miR-153, and to determine their possible interaction in triple negative and non triple negative breast cancer based on clinical outcome and the expression of BRCA1. 24 triple-negative and 13 non triple negative breast cancer cases, were studied by q-RT-PCR and immunohistochemistry to determine the expression of the four studied miRNAs and the BRCA1 protein, respectively. We observed that the BRCA1 protein was absent in 62.5% of the triple negative cases. Besides, the miR-146a and miR-26a were over expressed in triple negative breast cancer. These two miRNAs, miR-10b and miR-153 were significantly associated to lymph node metastases occurrence in triple negative breast carcinoma. All the analyzed microRNAs were not associated with the expression of BRCA1 in our conditions. Our work provides evidence that miR-146a, miR-26a, miR-10b and miR-153 could be defined as biomarkers in triple negative breast cancer to predict lymph node metastases (LNM).
Asunto(s)
Biomarcadores de Tumor/genética , MicroARNs/análisis , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/genética , Humanos , Metástasis Linfática/genética , Metástasis Linfática/patología , MicroARNs/biosíntesis , Persona de Mediana EdadRESUMEN
We compared the features of the Epstein-Barr virus (EBV) and Hodgkin lymphoma (HL) association in Tunisia in two periods of time, 1991-2001 (111 cases) and 2002-2012 (122 cases). The investigation of the EBV status by EBER in situ hybridization showed a significant decrease in the prevalence of EBV-positive HL from 69.3 % for the period 1991-2001 to 40.1 % for the 2002-2012 period (p = 0.00001). EBV positivity has decreased in all age groups but was more pronounced among young patients, in the 15-24-year age group (46.1 vs 10.3 %, p = 0.003), in the 25-34-year age group (56.2 vs 25 %, p = 0.04), and among children (88.4 vs 59.2 %, p = 0.01). This decrease in EBV-positive HL over time contrasted with a remarkable increase in EBV-negative HL in young adults aged 15-34 years (51.2 vs 83 %; p = 0.001), especially among women (59.1 vs 91.2 %; p = 0.01). The decrease in EBV-positive HL over time concerns particularly the nodular sclerosis histological subtype (69.2 vs 31.6 %, p = 0.000001). These results indicate that the epidemiology of HL and its association with EBV are changing over time, with a trend toward a Western profile, and point toward the emergence of other environmental causative factors, especially among young women, which remain to be identified.
Asunto(s)
Infecciones por Virus de Epstein-Barr/epidemiología , Herpesvirus Humano 4/genética , Enfermedad de Hodgkin/epidemiología , ARN Viral/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Comorbilidad , Infecciones por Virus de Epstein-Barr/diagnóstico , Infecciones por Virus de Epstein-Barr/virología , Femenino , Herpesvirus Humano 4/fisiología , Humanos , Hibridación in Situ , Masculino , Persona de Mediana Edad , Prevalencia , Factores de Tiempo , Túnez/epidemiología , Adulto JovenRESUMEN
PURPOSE: Hodgkin lymphoma (HL) is characterized by the presence of Hodgkin and Reed-Sternberg cells. Epstein-Barr virus (EBV) infection is thought to play an important role in the development of HL. Although epigenetic alterations, such as aberrant DNA methylation, are known to contribute to the pathogenesis of various malignancies, little is known about such alterations in HL and their putative relationships with EBV infection. METHODS: We investigated promoter methylation patterns of seven tumor-associated genes in 53 primary HL cases using methylation-specific PCR (MS-PCR). Concomitantly, the EBV infection status was assessed using PCR, in situ hybridization and immunohistochemistry. RESULTS: The gene promoter hypermethylation frequencies observed were 77.3 % for P16, 58.5 % for RASSF1A, 50.9 % for CDH1, 45.3 % for DAPK, 43.4 % for GSTP1, 37.7 % for SHP1 and 24.3 % for MGMT. SHP1 gene promoter hypermethylation was more frequently observed in patients at extreme ages (i.e., ≤ 15 and >54 years) than in adult patients (p = 0.006) and in patients with B symptoms (p = 0.03). Interestingly, most of the analyzed gene promoters were more frequently hypermethylated in EBV-negative than in EBV-positive cases, in particular the DAPK gene promoter (58 % versus 27 %, p = 0.04). Furthermore, hypermethylation of multiple gene promoters (≥ 3) was encountered more frequently in females than in males (86 % versus 57 %, p = 0.04), whereas EBV-positive cases were more common among males than females (55 % versus 30 %, p = 0.02). CONCLUSIONS: Our results indicate that epigenetic changes frequently occur in both EBV-positive and EBV-negative HL. The rates of these changes were found to vary according to clinico-pathological parameters. These observations probably reflect the multitude of factors involved in HL development and the complexity of their interactions with genetic and/or hormonal factors.
Asunto(s)
Metilación de ADN/genética , Infecciones por Virus de Epstein-Barr/complicaciones , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/virología , Adolescente , Adulto , Anciano , Niño , Femenino , Humanos , Inmunohistoquímica , Hibridación in Situ , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Regiones Promotoras Genéticas/genética , Adulto JovenRESUMEN
BACKGROUND: miR9 is an important tumor suppressor microRNA regulated by DNA methylation in various types of cancers. METHODS: We analyzed the methylation status of the 3 members of the miR9 family in 58 cases of Hodgkin lymphoma (HL) in comparison to 15 reactive lymph nodes. We also assessed the relationships between miR9 methylation and Epstein-Barr virus (EBV) infection and several clinicopathological parameters. RESULTS: We found that 84.5% of HL cases had a methylation in at least 1 of the 3 loci of miR9, whereas none of the nontumoral samples was methylated. The highest rate of methylation was found in miR9-2 (5q14.3) in 74.1% of the HL cases, followed by miR9-3 (15q26.1) in 56.9% and miR9-1 (1q22) in only 8.6% (p < 0.001). The promoter methylation of miR9-3 was more frequent in patients older than 15 years than in children (p = 0.02) and among women rather than men (p = 0.02). However, no significant correlation was found between miR9 methylation and EBV infection. CONCLUSION: These results indicate that miR9 methylation, especially miR9-2, is a frequent event in HL and may be involved in HL pathogenesis, irrespective of EBV infection.
Asunto(s)
Metilación de ADN , Enfermedad de Hodgkin/genética , MicroARNs/genética , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/virología , Femenino , Enfermedad de Hodgkin/patología , Enfermedad de Hodgkin/virología , Humanos , Masculino , Persona de Mediana Edad , Regiones Promotoras Genéticas , Factores Sexuales , Adulto JovenRESUMEN
PURPOSE: Several reports have indicated the presence of JC polyomavirus (JCV) in many human tumors, including colorectal cancers (CRCs). The presence of JCV infection in CRC patients has not been investigated in African countries. METHODS: We examined the prevalence and the biological significance of JCV in Tunisian CRC patients. The presence of JCV was assessed by polymerase chain reaction (PCR) in a series of 105 CRCs and 89 paired non-tumor colonic mucosa samples from Tunisian patients. Results were correlated with the clinicopathological features and immunohistochemical expression of ß-catenin, p53, and the proliferation marker Ki-67. RESULTS: JCV DNA was detected in 58.1% (61/105) of CRC and in only 14.6% (13/89) of paired non tumor colonic mucosa samples (p=0.03). The presence of JCV was significantly correlated with tumor differentiation (p=0.03). Moreover, JCV presence was significantly correlated with nuclear accumulation of ß-catenin (p=0.008) and p53 accumulation (p=0.0001). Multivariate logistic regression analysis showed that tumor differentiation, ß-catenin and p53 accumulation were independent parameters significantly associated with the presence of JCV in CRC (p=0.04; p=0.05; p=0.001, respectively). CONCLUSION: We support a role of JCV in colorectal carcinogenesis in Tunisian patients, especially of well differentiated morphology.
Asunto(s)
Adenocarcinoma Mucinoso/virología , Adenocarcinoma/virología , Neoplasias Colorrectales/virología , Virus JC/aislamiento & purificación , Infecciones por Polyomavirus/virología , Infecciones Tumorales por Virus/virología , Adenocarcinoma/química , Adenocarcinoma/epidemiología , Adenocarcinoma/patología , Adenocarcinoma Mucinoso/química , Adenocarcinoma Mucinoso/epidemiología , Adenocarcinoma Mucinoso/patología , Biomarcadores de Tumor/análisis , Estudios de Casos y Controles , Diferenciación Celular , Neoplasias Colorrectales/química , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/patología , ADN Viral/aislamiento & purificación , Femenino , Humanos , Inmunohistoquímica , Virus JC/genética , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Reacción en Cadena de la Polimerasa , Infecciones por Polyomavirus/epidemiología , Infecciones por Polyomavirus/metabolismo , Infecciones por Polyomavirus/patología , Prevalencia , Proteína p53 Supresora de Tumor/análisis , Infecciones Tumorales por Virus/epidemiología , Infecciones Tumorales por Virus/metabolismo , Infecciones Tumorales por Virus/patología , Túnez/epidemiología , beta Catenina/análisisRESUMEN
Deregulation of the microRNA miR124a by DNA methylation has been implicated in various malignancies, but no study reported its methylation status in Hodgkin lymphoma (HL). We evaluated the methylation of the three loci encoding for miR124a using methylation-specific PCR in 64 HL patients and 15 reactive lymph nodes obtained from patients with nonmalignant diseases. Results were correlated with clinicopathological parameters. Methylation rates of miR124a-1, miR124a-2, and miR124a-3 in HL were 17, 50, and 28%, respectively. None of the nontumoral samples showed aberrant hypermethylation in any of the miR tested. In HL cases, we found that miR124a-1 methylation correlates with high-risk International Prognostic Score (IPS) (score >3, p = 0.04) and that miR124a-2 methylation was more frequent in children (82.3%, p = 0.006) and men (63.9%, p = 0.01). Methylation of miR124a-3 was associated with advanced Ann-Arbor stages (p = 0.007). The survival analysis showed that methylation of at least one of the miR124a genes was associated with shortened event-free survival in univariate (p = 0.03) and multivariate (p = 0.02) analyses. These results suggest that miR124a methylation is associated with aggressive HL disease and may be an interesting factor for predicting treatment response.
Asunto(s)
Metilación de ADN , Enfermedad de Hodgkin/genética , MicroARNs/genética , Adolescente , Adulto , Supervivencia sin Enfermedad , Femenino , Enfermedad de Hodgkin/diagnóstico , Enfermedad de Hodgkin/patología , Humanos , Ganglios Linfáticos/patología , Masculino , Persona de Mediana Edad , Pronóstico , Adulto JovenRESUMEN
PURPOSE: Promoter hypermethylation and reduced expression of many genes have been found in gastric cancer. DNA methyltransferases are enzymes potentially affecting promoter hypermethylation. MATERIAL AND METHODS: We analyzed proteins expression of DNA methyltransferase 1 and 3b by immunohistochemistry in 47 surgically resected gastric cancer samples for which clinicopathological characteristics, patient's outcome and methylation status of 11 selected tumor-related genes have been determined. Promoter methylation status of genes was assessed by methylation specific PCR. RESULTS: We found that DNMT1 and 3b were up-regulated in gastric cancer and were detected in 51.1% and 57.4% of cases, respectively. Co-expression of DNMT1 and 3b was detected in 44.7%. Correlations analysis have showed that DNMT1 overexpression was significantly correlated with gastric cancer of intestinal histological type (P=0.01) and with gender of patient (P=0.01). However, there was no correlation between DNMT1 and DNMT3b overexpression in cancer and patients outcome. Moreover, there were no clear relations between the proteins expression of DNMT1 and 3b and DNA methylation status of genes. But co-expression of DNMT1 and DNMT3b was significantly associated with promoter hypermethylation of RAR-ß2 (P=0.04). CONCLUSIONS: Results from our study indicate that DNMT1 and 3b were overexpressed and could be involved in gastric tumorigenesis of intestinal histological type in the case of Tunisian patients.
Asunto(s)
ADN (Citosina-5-)-Metiltransferasas/metabolismo , Metilación de ADN/genética , Mucosa Intestinal/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , ADN (Citosina-5-)-Metiltransferasa 1 , ADN (Citosina-5-)-Metiltransferasas/genética , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Regiones Promotoras Genéticas/genética , ADN Metiltransferasa 3BRESUMEN
Aberrant DNA methylation on CpG islands is one of the most consistent epigenetic changes in human cancers, and the process of methylation is catalyzed by the DNA methyltransferases DNMT1, DNMT3a, and DNMT3b. Recent reports demonstrate that deregulation of miR-124a, one of the frequently methylated microRNAs in human cancers, is related to carcinogenesis. The aim of this study was to evaluate the frequencies of methylation of the three genomic loci encoding the miR-124a in primary breast cancers and to investigate their relationships with the clinicopathological characteristics of the tumors and with the expression levels of DNMT1, DNMT3a, and DNMT3b. The methylation status of the three genomic loci encoding the miR-124a (miR-124a-1, miR-124a-2, and miR-124a-3) was analyzed in fresh-frozen tumor samples using methylation-specific PCR in a large series of invasive breast ductal carcinomas (n = 60). Results were correlated to several clinicopathological characteristics of the tumors and to the expression levels of DNMT1, DNMT3a, and DNMT3b, determined by immunohistochemistry. Promoter hypermethylation of miR-124a-1, miR-124a-2, and miR-124a-3 was detected in 53.3, 70, and 36.7% of cases, respectively. Methylation of miR-124a-2 correlated to patients with age higher than 45 years (P = 0.008) and to postmenopausal patients (P = 0.03), whereas methylation of miR-124a-3 correlated significantly to tumor size >20 mm (P = 0.03). Interestingly, simultaneous methylation of the three genes encoding miR-124a correlated significantly with the presence of lymph node metastasis (P = 0.01) and high mitotic score (P = 0.03). No significant correlation was found between promoter hypermethylation of miR-124a and expression of hormone receptors or HER2/neu. With regard to DNMT expression, no correlation was found between DNMT1 or DNMT3a expression and promoter methylation of any tested microRNA. However, DNMT3b overexpression correlates significantly with the hypermethylation of miR-124a-3 (P = 0.03). Our data indicates that miR-124a-1, miR-124a-2, and miR-124a-3 genes are frequently methylated in breast cancer and play a role in tumor growth and aggressivity.
Asunto(s)
Neoplasias de la Mama/genética , Metilación de ADN , MicroARNs/genética , Adulto , Anciano , Neoplasias de la Mama/patología , ADN (Citosina-5-)-Metiltransferasa 1 , ADN (Citosina-5-)-Metiltransferasas/análisis , ADN (Citosina-5-)-Metiltransferasas/genética , ADN Metiltransferasa 3A , Progresión de la Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Regiones Promotoras Genéticas , ADN Metiltransferasa 3BRESUMEN
The aim of this study is to evaluate tropomyosin-4 (TM4) expression in infiltrating ductal breast carcinomas (IDCAs), as well as its prognostic significance. Using a 2-DE/MALDI-TOF mass spectrometry investigation coupled with an immunohistochemical approach, we have assessed the expression of TM4 in IDCAs, as well as in other types of breast tumors. Proteomic analyses revealed an increased expression of tropomyosin-4 in IDCA tumors. Using immunohistochemistry, overexpression of tropomyosin-4 was confirmed in 51 additional tumor specimens. Statistical analyses revealed, however, no significant correlations between tropomyosin-4 expression and clinicopathological parameters of the disease including tumor stage, patient age, estrogen and progesterone receptor status, and lymph node metastasis occurrence. A significant association was found, however, with a high Scarf-Bloom-Richardson (SBR) grade, a known marker of tumor severity. Additionally, the SBR component showing a correlation with TM4 expression was the tubular differentiation status. This study demonstrates the upregulation of tropomyosin-4 in IDCA tissues, which may highlight its involvement in breast cancer development. Our findings also support a link between tropomyosin-4 expression and aggressiveness of IDCA tumors.
Asunto(s)
Neoplasias de la Mama/metabolismo , Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Tropomiosina/metabolismo , Adulto , Secuencia de Aminoácidos , Western Blotting , Mama/patología , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Electroforesis en Gel Bidimensional , Femenino , Humanos , Inmunohistoquímica , Metástasis Linfática , Datos de Secuencia Molecular , Clasificación del Tumor , Estadificación de Neoplasias , Proteoma/metabolismo , Proteómica/métodos , Índice de Severidad de la Enfermedad , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Regulación hacia ArribaRESUMEN
The aim of this study was to evaluate calreticulin expression in infiltrating ductal breast carcinomas (IDCAs), as well as its relationships with clinicopathological parameters of the disease. Using a two-dimensional gel electrophoresis/matrix-assisted laser desorption ionization time of flight mass spectrometry investigation coupled to an immunohistochemical approach, we have assessed the expression of calreticulin in IDCAs, as well as in other types of breast tumors. The humoral immune response against calreticulin was estimated using a serological proteomics-based strategy. Proteomic analyses revealed an increased expression of calreticulin in IDCA tumors. Using immunohistochemistry, overexpression of calreticulin was confirmed in 51 additional tumor specimens. Statistical analyses revealed, however, no significant correlations between calreticulin expression and clinicopathological parameters of the disease including tumor stage, patient age, SBR grade, and lymph node metastasis occurrence. A significant association was found, however, with estrogen receptor status. This study demonstrates the upregulation of calreticulin in IDCA tissues which may highlight its involvement in breast cancer development. Our findings also support a link between calreticulin expression and estrogen transduction pathways. Our results do not, however, support the involvement of calreticulin in the development of a humoral immune response in IDCAs.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Calreticulina/metabolismo , Carcinoma Ductal de Mama/metabolismo , Inmunidad Humoral/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/inmunología , Carcinoma Ductal de Mama/patología , Progresión de la Enfermedad , Electroforesis en Gel Bidimensional , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , Proteómica , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
This study aims to evaluate αB-crystallin expression in infiltrating ductal breast carcinomas (IDCAs), as well as, its prognostic significance. Using a two-dimensional electrophoresis matrix-assisted laser desorption/ionisation-time of flight mass spectrometry investigation coupled to an immunohistochemical approach, we have assessed the expression of αB-crystallin in IDCAs, as well as, in other types of breast tumors (invasive lobular carcinomas, medullary carcinomas, and in situ ductal carcinomas). Correlation between αB-crystallin expression and clinicopathological parameters of breast cancer has also been investigated. Proteomic analyses revealed an increased expression of αB-crystallin in IDCA tumors compared to adjacent nontumor tissues. Overexpression of this molecular chaperone was further confirmed in 51 tumor specimens. Statistical analyses revealed, however, no significant correlations between αB-crystallin expression and clinicopathological parameters of the disease (tumor stage, patient age, hormone receptors, SBR grade, and lymph node metastases). This study demonstrates the upregulation of αB-crystallin in IDCA tissues which may highlight its possible involvement in breast cancer development. Our findings do not, however, support the involvement of this molecular chaperone in the progression of this disease.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Cadena B de alfa-Cristalina/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Mama/patología , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Estudios de Casos y Controles , Electroforesis en Gel Bidimensional , Femenino , Humanos , Técnicas para Inmunoenzimas , Metástasis Linfática , Persona de Mediana Edad , Clasificación del Tumor , Pronóstico , Proteómica , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
OBJECTIVES: To determine the clinical significance of α1-proteinase inhibitor (α1-Pi) in infiltrating ductal breast carcinoma patients. DESIGN AND METHODS: Serum levels of α1-Pi, tryptic specific inhibitory capacity and α1-Pi circulating immune complexes were determined using radial immunodiffusion, BAPNA assays and ELISA, respectively. 2-DE-MS and immunohistochemistry were performed to examine α1-Pi protein expression. RESULTS: A decreased serum level of α1-Pi was found among breast cancer patients in comparison to controls. In addition, we found a significantly decreased mean level of α1-Pi in the node metastatic group when compared to node negative patients. However, the functional activity of the inhibitor did not decrease proportionately. Through 2-DE analyses, a differential expression of α1-Pi isoforms according to tumor stage and node metastatic development was found. CONCLUSIONS: Both α1-Pi levels and specific activity could be a source of complementary clinical information and may provide useful information for a better understanding of the mechanisms of metastasis.
Asunto(s)
Antígenos de Neoplasias/sangre , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/sangre , Carcinoma Ductal de Mama/sangre , alfa 1-Antitripsina/sangre , Adulto , Secuencia de Aminoácidos , Antígenos de Neoplasias/inmunología , Área Bajo la Curva , Biomarcadores de Tumor/química , Biomarcadores de Tumor/inmunología , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/inmunología , Carcinoma Ductal de Mama/secundario , Estudios de Casos y Controles , Femenino , Humanos , Metástasis Linfática , Persona de Mediana Edad , Datos de Secuencia Molecular , Fragmentos de Péptidos/química , Isoformas de Proteínas/sangre , Isoformas de Proteínas/inmunología , Proteolisis , Curva ROC , Tripsina/química , Inhibidores de Tripsina/sangre , Inhibidores de Tripsina/inmunología , alfa 1-Antitripsina/química , alfa 1-Antitripsina/inmunología , alfa 1-Antitripsina/metabolismoRESUMEN
DNA methyltransferase 1, 3a, and 3b affect DNA methylation, and it is thought that they play an important role in the malignant transformation of various cancers. The current study was designed to analyze DNA methyltransferase expression by immunohistochemistry in a series of 94 Tunisian sporadic breast carcinomas. Results were correlated to clinicopathologic parameters and promoter methylation status of 8 tumor suppressor genes (BRCA1, BRCA2, RASSFA1, TIMP3, CDH1, P16, RARß2, and DAPK). Overexpression of DNA methyltransferase 1, 3a, and 3b was detected in 46.8%, 32%, and 44.7% of cases, respectively. A significant correlation was found between DNA methyltransferase 1 overexpression and Scarff-Bloom-Richardson histologic grade III (P = .01). DNA methyltransferase 3a overexpression was significantly associated with menopausal status (P = .01), Scarff-Bloom-Richardson histologic grade III (P = .0001), estrogen (P = .04) and progesterone (P = .007) receptor negativity, and HER2 overexpression (P = .004). However, DNA methyltransferase 3a overexpression was found less frequently in the luminal A intrinsic breast cancer subtype (9.7%) than in luminal B (53%), HER2 (41%), and triple-negative (50%) subtypes (P = .001). DNA methyltransferase 3b overexpression shows significant correlation with promoter hypermethylation of BRCA1 (P = .03) and RASSFA1 (P = .04) and with the hypermethylator phenotype (more than 4 methylated genes, P = .01). These data suggest that overexpression of various DNA methyltransferases might represent a critical event responsible for the epigenetic inactivation of multiple tumor suppressor genes, leading to the development of aggressive forms of sporadic breast cancer.
Asunto(s)
Neoplasias de la Mama/enzimología , Carcinoma Ductal de Mama/enzimología , ADN (Citosina-5-)-Metiltransferasas/biosíntesis , Adulto , Anciano , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patología , ADN (Citosina-5-)-Metiltransferasa 1 , ADN (Citosina-5-)-Metiltransferasas/análisis , Metilación de ADN , ADN Metiltransferasa 3A , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Reacción en Cadena de la Polimerasa , Regiones Promotoras Genéticas , Túnez , Regulación hacia Arriba , ADN Metiltransferasa 3BRESUMEN
We have previously showed the presence of the simian virus 40 (SV40) and the mouse mammary tumor virus (MMTV)-like in a significant proportions of Tunisian breast carcinomas. However, to date there are no published studies concerning evaluation of the possible implication of the human polyomaviruses JC (JCV) and BK (BKV) in breast carcinomas. The presence of JCV and BKV DNA was investigated by PCR in a 123 primary breast carcinomas and matched adjacent non-tumor breast tissues. The results were correlated to clinicopathological and virological parameters. JCV T-antigen DNA was detected in 23% of breast carcinoma cases; however, all cases were negative for BKV. JCV T antigen PCR products were further confirmed as authentic JCV genome by direct sequencing. JCV was found in invasive ductal carcinomas (28/112 cases) but not in invasive lobular carcinomas (0/5) or medullary carcinomas (0/6). JCV DNA presence correlates inversely with the expression of estrogen (P = 0.022) and progesterone (P = 0.008) receptors. JCV DNA presence correlates also with "triple negative" phenotype (P = 0.021). With regard to virological data, a trend toward an inverse correlation was noted between the presence of JCV and SV40 (P = 0.06). Moreover, significant correlation was found between multiple viral infection (JCV, and/or SV40, and/or MMTV-like in the same tumor) and "triple negative" phenotype (P = 0.001) and also with p53 accumulation (P = 0.028). To the best of our knowledge, this is the first study demonstrating the presence of JCV in a subset of breast carcinomas. Also our results suggest that "triple negative" breast carcinomas are viral-related tumors.
Asunto(s)
Virus BK/genética , Neoplasias de la Mama/virología , Carcinoma/virología , Virus JC/genética , Adulto , Anciano , Virus BK/metabolismo , Secuencia de Bases , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/mortalidad , Carcinoma/diagnóstico , Carcinoma/mortalidad , Transformación Celular Viral/genética , ADN Viral , Femenino , Humanos , Virus JC/metabolismo , Persona de Mediana Edad , Datos de Secuencia Molecular , Estadificación de Neoplasias , Alineación de Secuencia , Túnez , Adulto JovenRESUMEN
Breast carcinoma is a major cause of death among women, and the potential implication of viruses in its pathogenesis remains worth a hypothesis. The potential role of Epstein-Barr virus (EBV) in its pathogenesis is still a subject of continued discussion and investigation. The aim of this study was to evaluate the prevalence of EBV in sporadic breast cancers in Tunisia, and to determine the clinicopathological characteristics of virus-positive cases. Viral presence has been evaluated by polymerase chain reaction (PCR), in situ hybridization, and immunohistochemistry investigated on tumor tissues and their corresponding normal breast tissues collected from 123 Tunisian women with sporadic breast carcinomas. Viral status in tumors was then correlated with various clinicopathological parameters. Using specific PCR assays, EBV DNA was found in 33 (27%) out of 123 breast carcinoma cases. EBV-encoded small RNAs (EBERs) in situ hybridization was negative in the neoplastic cells, but stomal lymphocytes were positive in 4 cases. Immunohistochemistry for latent membrane protein 1 (LMP1) was negative in all cases. None of the normal breast tissues showed positive results for EBV using PCR, in situ hybridization, and immunohistochemistry. A correlation was found between EBV DNA presence and the negativity of estrogen receptor (P=0.008). However, no significant correlation was found for the other parameters investigated, including patient age, Scarff-Bloom-Richardson (SBR) histological grade, tumor size, and histological node involvement. With regard to survival data, overall and disease-free survivals were shorter in EBV-positive breast carcinoma cases than in EBV-negative ones, but this difference did not reach statistical significance. Our study indicates the presence of EBV DNA in a significant proportion of breast cancer in Tunisia. Further studies are required to elucidate the role of this virus in breast carcinogenesis.
Asunto(s)
Neoplasias de la Mama/virología , ADN Viral/análisis , Infecciones por Virus de Epstein-Barr/epidemiología , Herpesvirus Humano 4/aislamiento & purificación , Proteínas de la Matriz Viral/metabolismo , Neoplasias de la Mama/patología , ADN Viral/genética , Supervivencia sin Enfermedad , Infecciones por Virus de Epstein-Barr/patología , Infecciones por Virus de Epstein-Barr/virología , Femenino , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , Humanos , Inmunohistoquímica , Hibridación in Situ , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Prevalencia , Túnez/epidemiologíaRESUMEN
La tumeur myofibroblastique inflammatoire est une lésion classée par l'OMS parmi les néoplasies intermédiaires. Elle peut siéger dans différents organes : les poumons, le pancréas, le mésentère et l'utérus. La localisation vésicale est rare.Nous rapportons le cas d'un jeune homme de 38 ans qui a consulté pour hématurie. L'échographie a révélé la présence d'une structure tissulaire intravésicale de 3 cm de grand axe. L'examen anatomopathologique et l'étude immunohistochimique ont conclu à une tumeur myofibroblastique inflammatoire de la vessie. À partir de cette observation, nous présentons les diagnostics différentiels et les particularités anatomopathologiques de cette localisation rare.Myofibroblastic inflammatory tumor is considered as an intermediate neoplasm according to the WHO classification. It can occur in different organs: lung, pancreas, mesentery and uterus. The localization in the bladder is unusual. We report a case of a 38-year-old patient who presented with hematuria. Echography showed a 3 cm tissular structure of the bladder. Histological analysis and immunohistochemistry concluded to the diagnosis of myofibroblastic tumor of the bladder. The present work will give a general view of the myofibroblastic tumor, and will review its differential diagnosis.