RESUMEN
Some transcripts that are not translated into proteins can be encoded by the mammalian genome. Long noncoding RNAs (lncRNAs) are noncoding RNAs that can function as decoys, scaffolds, and enhancer RNAs and can regulate other molecules, including microRNAs. Therefore, it is essential that we obtain a better understanding of the regulatory mechanisms of lncRNAs. In cancer, lncRNAs function through several mechanisms, including important biological pathways, and the abnormal expression of lncRNAs contributes to breast cancer (BC) initiation and progression. BC is the most common type of cancer among women worldwide and has a high mortality rate. Genetic and epigenetic alterations that can be regulated by lncRNAs may be related to early events of BC progression. Ductal carcinoma in situ (DCIS) is a noninvasive BC that is considered an important preinvasive BC early event because it can progress to invasive BC. Therefore, the identification of predictive biomarkers of DCIS-invasive BC progression has become increasingly important in an attempt to optimize the treatment and quality of life of patients. In this context, this review will address the current knowledge about the role of lncRNAs in DCIS and their potential contribution to the progression of DCIS to invasive BC.
Asunto(s)
Neoplasias de la Mama , Carcinoma in Situ , Carcinoma Intraductal no Infiltrante , ARN Largo no Codificante , Animales , Humanos , Femenino , Carcinoma Intraductal no Infiltrante/genética , Carcinoma Intraductal no Infiltrante/patología , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Calidad de Vida , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Carcinoma in Situ/genética , Epigénesis Genética , Mamíferos/metabolismoRESUMEN
Long intergenic non-protein coding RNA 885 (LINC00885) was identified as significantly upregulated in breast ductal carcinoma in situ (DCIS). The aim of this study was to characterize the phenotypic effects and signaling pathways modulated by LINC00885 in non-invasive and invasive breast cancer models. We determined that LINC00885 induces premalignant phenotypic changes by increasing cell proliferation, motility, migration and altering 3D growth in normal and DCIS breast cell lines. Transcriptomic studies (RNA-seq) identified the main signaling pathways modulated by LINC00885, which include bioprocesses related to TP53 signaling pathway and proliferative signatures such as activation of EREG, EGFR and FOXM1 pathways. LINC00885 silencing in breast cancer lines overexpressing this lncRNA leads to downregulation of proliferation related transcripts such as EREG, CMYC, CCND1 and to significant decrease in cell migration and motility. TCGA-BRCA data analyses show an association between high LINC00885 expression and worse overall survival in patients with primary invasive breast carcinomas (p = 0.024), suggesting that the pro-tumorigenic effects of LINC00885 overexpression persist post-invasion. We conclude that LINC00885 behaves as a positive regulator of cell growth both in normal and DCIS breast cells possibly operating as a ceRNA and representing a novel oncogenic lncRNA associated with early stage breast cancer progression.
Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Carcinoma Intraductal no Infiltrante/genética , Carcinoma Intraductal no Infiltrante/metabolismo , Progresión de la Enfermedad , Oncogenes , ARN Largo no Codificante/genética , Neoplasias de la Mama/patología , Carcinogénesis/genética , Carcinoma Intraductal no Infiltrante/patología , Movimiento Celular/genética , Proliferación Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Humanos , Células MCF-7 , Invasividad Neoplásica/genética , Estadificación de Neoplasias , Interferencia de ARN , ARN Largo no Codificante/metabolismo , Transcriptoma , Regulación hacia Arriba/genéticaRESUMEN
BACKGROUND: Ductal carcinoma in situ is a non-obligate precursor of invasive breast carcinoma and presents a potential risk of over or undertreatment. Finding molecular biomarkers of disease progression could allow for more adequate patient treatment. We aimed to identify potential biomarkers that can predict invasiveness risk. METHODS: In this epithelial cell-based study archival formalin-fixed paraffin-embedded blocks from six patients diagnosed with invasive lesions (pure invasive ductal carcinoma), six with in-situ lesions (pure ductal carcinoma in situ), six with synchronous lesions (invasive ductal carcinoma with an in-situ component) and three non-neoplastic breast epithelium tissues were analyzed by gene expression profiling of 770 genes, using the nCounter® PanCancer Pathways panel of NanoString Technologies. RESULTS: The results showed that in comparison with non-neoplastic tissue the pure ductal carcinoma in situ was one with the most altered gene expression profile. Comparing pure ductal carcinoma in situ and in-situ component six differentially expressed genes were found, three of them (FGF2, GAS1, and SFRP1), play a role in cell invasiveness. Importantly, these genes were also differentially expressed between invasive and noninvasive groups and were negatively regulated in later stages of carcinogenesis. CONCLUSIONS: We propose these three genes (FGF2, GAS1, and SFRP1) as potential biomarkers of ductal carcinoma in situ progression, suggesting that their downregulation may be involved in the transition of stationary to migrating invasive epithelial cells.
Asunto(s)
Biomarcadores de Tumor , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Intraductal no Infiltrante/diagnóstico , Anciano , Anciano de 80 o más Años , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Carcinoma Intraductal no Infiltrante/genética , Carcinoma Intraductal no Infiltrante/metabolismo , Biología Computacional , Progresión de la Enfermedad , Susceptibilidad a Enfermedades , Femenino , Perfilación de la Expresión Génica , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Mapeo de Interacción de Proteínas , Mapas de Interacción de Proteínas , TranscriptomaRESUMEN
Ductal carcinoma in situ (DCIS) is a noninvasive precursor lesion to invasive breast carcinoma. We still have no understanding on why only some DCIS lesions evolve to invasive cancer whereas others appear not to do so during the life span of the patient. Here, we performed full exome (tumor vs. matching normal), transcriptome, and methylome analysis of 30 pure high-grade DCIS (HG-DCIS) and 10 normal breast epithelial samples. Sixty-two percent of HG-DCIS cases displayed mutations affecting cancer driver genes or potential drivers. Mutations were observed affecting PIK3CA (21% of cases), TP53 (17%), GATA3 (7%), MLL3 (7%) and single cases of mutations affecting CDH1, MAP2K4, TBX3, NF1, ATM, and ARID1A. Significantly, 83% of lesions displayed numerous large chromosomal copy number alterations, suggesting they might precede selection of cancer driver mutations. Integrated pathway-based modeling analysis of RNA-seq data allowed us to identify two DCIS subgroups (DCIS-C1 and DCIS-C2) based on their tumor-intrinsic subtypes, proliferative, immune scores, and in the activity of specific signaling pathways. The more aggressive DCIS-C1 (highly proliferative, basal-like, or ERBB2(+)) displayed signatures characteristic of activated Treg cells (CD4(+)/CD25(+)/FOXP3(+)) and CTLA4(+)/CD86(+) complexes indicative of a tumor-associated immunosuppressive phenotype. Strikingly, all lesions showed evidence of TP53 pathway inactivation. Similarly, ncRNA and methylation profiles reproduce changes observed postinvasion. Among the most significant findings, we observed upregulation of lncRNA HOTAIR in DCIS-C1 lesions and hypermethylation of HOXA5 and SOX genes. We conclude that most HG-DCIS lesions, in spite of representing a preinvasive stage of tumor progression, displayed molecular profiles indistinguishable from invasive breast cancer.
Asunto(s)
Neoplasias de la Mama/genética , Carcinoma Intraductal no Infiltrante/química , Metilación de ADN , ADN de Neoplasias/genética , Perfilación de la Expresión Génica , Proteínas de Neoplasias/genética , Transcriptoma , Antígenos de Diferenciación de Linfocitos T/análisis , Mama/química , Neoplasias de la Mama/química , Neoplasias de la Mama/inmunología , Antígeno CTLA-4/análisis , Carcinoma Intraductal no Infiltrante/clasificación , Carcinoma Intraductal no Infiltrante/genética , Carcinoma Intraductal no Infiltrante/inmunología , Femenino , Regulación Neoplásica de la Expresión Génica , Genes Relacionados con las Neoplasias , Humanos , Linfocitos Infiltrantes de Tumor/química , Linfocitos Infiltrantes de Tumor/inmunología , Mutación , Invasividad Neoplásica/genética , Proteínas de Neoplasias/análisis , ARN Mensajero/genética , ARN Neoplásico/genética , ARN no Traducido/genética , Linfocitos T Reguladores/inmunologíaRESUMEN
Increased sialylation and ß1,6-branched oligosaccharides has been associated with a variety of structural changes in cell surface carbohydrates, most notably in tumorigenesis. Lectins are defined as proteins that preferentially recognize and bind carbohydrate complexes protruding from glycolipids and glycoproteins. This interaction with carbohydrates can be as specific as the interaction between antigen and antibody. Due to this type of interaction lectins have been used as experimental auxiliary tools in histopathological diagnosis of cancer. This study was designed to evaluate the differential expression of sialic acids and ß1,6-N-acetylglucosaminyltransferase V (MGAT5) in invasive (IDC) and in situ (DCIS) ductal carcinoma of the breast and its possible application as prognostic biomarkers. A possible transition between pre-malign and malign lesions was evaluated using DCIS samples. Biopsies were analyzed regarding the expression of MUC1, p53, Ki-67, estrogen receptor, progesterone receptor, HER-2 and MGAT5. α2,6-linked sialic acids residues recognized by SNA lectin was overexpressed in 33.3% of IDC samples and it was related with Ki-67 (p=0.042), PR (p=0.029), lymphnodes status (p=0.017) and death (p=0.011). Regarding survival analysis SNA was the only lectin able to correlate with specific-disease survival and disease-free survival (p=0.024 and p=0.041, respectively), besides, it presents itself as an independent variable by Cox Regression analysis (p= 0.004). Comparing IDC and DCIS cases, only SNA showed different staining pattern (p=0.034). The presence of sialic acids on tumor cell surface can be an indicative of poor prognosis and our study provides further evidence that SNA lectin can be used as a prognostic probe in IDC and DCIS patients.
Asunto(s)
Biomarcadores de Tumor/análisis , Neoplasias de la Mama/enzimología , Carcinoma Ductal de Mama/enzimología , Carcinoma Intraductal no Infiltrante/enzimología , Inmunohistoquímica , N-Acetilglucosaminiltransferasas/análisis , Lectinas de Plantas , Proteínas Inactivadoras de Ribosomas , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/mortalidad , Carcinoma Ductal de Mama/patología , Carcinoma Intraductal no Infiltrante/genética , Carcinoma Intraductal no Infiltrante/mortalidad , Carcinoma Intraductal no Infiltrante/patología , Distribución de Chi-Cuadrado , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Invasividad Neoplásica , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Factores de Riesgo , Factores de Tiempo , Análisis de Matrices TisularesRESUMEN
The spread of mammographic screening programmes around the world, including in developing countries, has substantially contributed to the diagnosis of small non-palpable lesions, which has increased the detection rate of DCIS (ductal carcinoma in situ). DCIS is heterogeneous in several ways, such as its clinical presentation, morphology and genomic profile. Excellent outcomes have been reported; however, many questions remain unanswered. For example, which patients groups are overtreated and could instead benefit from minimal intervention and which patient groups require a more traditional multidisciplinary approach. The development of a comprehensive integrated analysis that includes the radiological, morphological and genetic aspects of DCIS is necessary to answer these questions. This review focuses on discussing the significant findings about the morphological and molecular features of DCIS and its progression that have helped to uncover the biological and genetic heterogeneity of this disease. The knowledge gained in recent years might allow the development of tailored clinical management for women with DCIS in the future.
Asunto(s)
Neoplasias de la Mama , Carcinoma Intraductal no Infiltrante , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Carcinoma Intraductal no Infiltrante/genética , Carcinoma Intraductal no Infiltrante/metabolismo , Carcinoma Intraductal no Infiltrante/patología , Carcinoma Intraductal no Infiltrante/terapia , Femenino , HumanosRESUMEN
Breast carcinoma is one of the most common neoplasia and the first cause of women cancer related deaths worldwide. In the past few years with diagnostic increment, the number of patients diagnosed with ductal carcinoma in situ (DCIS) increased considerably and opened up new ways in research and new dilemmas in diagnostic and clinical practice. This work aimed to evaluate differences in Galectin-1 and Galectin-3 expression and lectins ligands profile on DCIS cells in hypoxic microenvironment. Lectin histochemistry and immunohistochemistry were performed with Concanavalin A, Wheat Germ Agglutinin, Peanut Agglutinin and Ulex europaeus Agglutinin lectins and with anti-Galectin-1 and anti-Galectin-3 antibodies. Lectin ligands were more recognized in hypoxic lesions by Concanavalin A (p = 0.0019), Wheat Germ Agglutinin (p < 0.001) and Ulex europaeus Agglutinin (p = 0.0014), but not by Peanut Agglutinin (p = 0.5779) when compared to non-hypoxic. Galectin-1 was not observed in all cases analyzed on both groups, differing from Galectin-3 that was overexpressed on cytoplasm of DCIS hypoxic group in relation to control group (p = 0.031). As far as we are concerned, this is the first paper that describes glycobiological alterations in breast cancer hypoxic environment in vivo that could be used to validate in vitro models on this aspect. Moreover, comedogenic/necrotic carcinomas were usually associated with poor-prognostic than others, and our results show that glycosylation may play an important role in this event.
Asunto(s)
Neoplasias de la Mama/metabolismo , Carcinoma Intraductal no Infiltrante/metabolismo , Hipoxia/metabolismo , Microambiente Tumoral/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Carcinoma Intraductal no Infiltrante/genética , Carcinoma Intraductal no Infiltrante/patología , Femenino , Galectina 1/biosíntesis , Galectina 3/biosíntesis , Regulación Neoplásica de la Expresión Génica , Humanos , Hipoxia/patología , Inmunohistoquímica , Lectinas/metabolismoRESUMEN
Caveolin-1 (Cav-1) is a structural protein present in invaginations of the cell membrane. In human breast cancer, the cav-1 gene is believed to be a tumor suppressor gene associated with inhibition of tumor metastasis. However, little is known about its expression, regulation and function in canine mammary tumors. Expression levels of cav-1 were investigated using real-time PCR and immunohistochemical detection with an anti-human Cav-1 antibody. Gene expression stability of different samples was analyzed using the geNorm software. Mammary tumors from 51 female dogs were compared to normal mammary tissue from 10 female dogs. Malignant mammary cells showed a loss of Cav-1 expression by quantitative RT-PCR and weak Cav-1 staining by immunohistochemistry compared to normal mammary gland tissue. There was a significant relationship between outcome and immunostaining as well as with tumor size, indicating that caveolin subexpression has a positive predictive value and is related to higher survival and smaller tumor size. Our findings indicate that Cav-1 is a potential prognostic marker for canine mammary tumors.
Asunto(s)
Caveolina 1/metabolismo , Perros/genética , Glándulas Mamarias Animales/metabolismo , Neoplasias Mamarias Animales/metabolismo , Animales , Carcinoma Intraductal no Infiltrante/genética , Carcinoma Intraductal no Infiltrante/metabolismo , Carcinoma Intraductal no Infiltrante/patología , Carcinoma Intraductal no Infiltrante/veterinaria , Caveolina 1/genética , Membrana Celular/metabolismo , Membrana Celular/patología , Enfermedades de los Perros/genética , Enfermedades de los Perros/metabolismo , Enfermedades de los Perros/patología , Femenino , Glándulas Mamarias Animales/patología , Neoplasias Mamarias Animales/genética , Neoplasias Mamarias Animales/patología , Proteínas de la Membrana/metabolismo , Metástasis de la Neoplasia , Pronóstico , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
INTRODUCTION: Ductal carcinoma in situ (DCIS) is considered to be related to the development of invasive breast cancer. The aim of molecular biological research of preinvasive breast lesion characteristics and comparison with normal tissues and tissue of invasive tumours is to identify patients at high risk of developing invasive tumour on the basis of already established preinvasive lesions, and thus influence clinical decision-making. The aim of our study was to analyse several key molecules involved in different cellular pathways important for cancer development and progression in different types of breast tissue and to describe similarities and differences between premalignant and malignant lesions. MATERIAL AND METHODS: Genetic material isolated from both the tumour and healthy tissue was examined by loss of heterozygosity (LOH) analysis and real-time PCR using collagen 2A as a house-keeping gene. RESULTS: We analysed 65 samples of healthy mammary gland, 25 DCIS and 42 invasive ductal breast cancer samples. We analysed the LOH in three genes: BRCA1, BRCA2 and p53; and the gene expression of the VEGF gene and Bcl-2 gene. LOH in the BRCA1 gene was present in 44.74% of invasive samples and in 8.69% of DCIS (p=0.026); LOH in the BRCA2 gene in 45.0% of invasive samples and in 9.52% of DCIS (p=0.036); LOH in the p53 gene in 32.5% of invasive samples and in 31.82% of DCIS (p=0.97). No LOH was observed in normal tissue samples. VEGF was overexpressed in 14.3% of invasive cancers and in 12.0% of DCIS. Overexpression of Bcl-2 was observed in 11.9% of invasive cancers and in 8.0% of DCIS. CONCLUSION: We have confirmed that some of the molecular characteristics of DCIS are identical to those of invasive carcinoma. This approach could lead to the identification of molecular markers as indicators for the potential development of DCIS into invasive carcinoma or identification of DCIS subgroups with latent invasion.
Asunto(s)
Neoplasias de la Mama/genética , Carcinoma Ductal de Mama/genética , Carcinoma Intraductal no Infiltrante/genética , Perfilación de la Expresión Génica , Pérdida de Heterocigocidad , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Carcinoma Intraductal no Infiltrante/patología , Análisis Mutacional de ADN , Femenino , Regulación Neoplásica de la Expresión Génica , Genes BRCA1 , Genes BRCA2 , Genes bcl-2 , Genes p53 , Humanos , Pérdida de Heterocigocidad/genética , Invasividad NeoplásicaRESUMEN
INTRODUCTION: Ductal carcinoma in situ (DCIS) of the breast includes a heterogeneous group of preinvasive tumors with uncertain evolution. Definition of the molecular factors necessary for progression to invasive disease is crucial to determining which lesions are likely to become invasive. To obtain insight into the molecular basis of DCIS, we compared the gene expression pattern of cells from the following samples: non-neoplastic, pure DCIS, in situ component of lesions with co-existing invasive ductal carcinoma, and invasive ductal carcinoma. METHODS: Forty-one samples were evaluated: four non-neoplastic, five pure DCIS, 22 in situ component of lesions with co-existing invasive ductal carcinoma, and 10 invasive ductal carcinoma. Pure cell populations were isolated using laser microdissection. Total RNA was purified, DNase treated, and amplified using the T7-based method. Microarray analysis was conducted using a customized cDNA platform. The concept of molecular divergence was applied to classify the sample groups using analysis of variance followed by Tukey's test. RESULTS: Among the tumor sample groups, cells from pure DCIS exhibited the most divergent molecular profile, consequently identifying cells from in situ component of lesions with co-existing invasive ductal carcinoma as very similar to cells from invasive lesions. Additionally, we identified 147 genes that were differentially expressed between pure DCIS and in situ component of lesions with co-existing invasive ductal carcinoma, which can discriminate samples representative of in situ component of lesions with co-existing invasive ductal carcinoma from 60% of pure DCIS samples. A gene subset was evaluated using quantitative RT-PCR, which confirmed differential expression for 62.5% and 60.0% of them using initial and partial independent sample groups, respectively. Among these genes, LOX and SULF-1 exhibited features that identify them as potential participants in the malignant process of DCIS. CONCLUSIONS: We identified new genes that are potentially involved in the malignant transformation of DCIS, and our findings strongly suggest that cells from the in situ component of lesions with co-existing invasive ductal carcinoma exhibit molecular alterations that enable them to invade the surrounding tissue before morphological changes in the lesion become apparent.
Asunto(s)
Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Carcinoma Intraductal no Infiltrante/patología , Perfilación de la Expresión Génica , Genes Relacionados con las Neoplasias , Proteínas de Neoplasias/biosíntesis , Adulto , Anciano , Neoplasias de la Mama/química , Neoplasias de la Mama/genética , Carcinoma Ductal de Mama/química , Carcinoma Ductal de Mama/genética , Carcinoma Intraductal no Infiltrante/química , Carcinoma Intraductal no Infiltrante/genética , Progresión de la Enfermedad , Femenino , Humanos , Microdisección , Persona de Mediana Edad , Invasividad Neoplásica/genética , Proteínas de Neoplasias/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteína-Lisina 6-Oxidasa/genética , ARN Mensajero/biosíntesis , ARN Mensajero/genética , ARN Neoplásico/biosíntesis , ARN Neoplásico/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sulfotransferasas/genética , Factores de TiempoRESUMEN
One hundred and three consecutive cases of breast cancer in Trinidadian women were evaluated for steroid receptor status and c-erbB-2 receptor along with conventional parameters including age, ethnicity, tumour size, histological type and grade, and lymph node status: The molecular markers were studied by immunohistochemistry (IHC) on paraffin sections. Tumour size > 2 cm was seen in 60% of the cases. Oestrogen receptor (ER), progesterone receptor (PR) and c-erbB-2 showed 54%, 46% and 63% positivity, respectively. There was no correlation between c-erbB-2 and steroid receptors. Forty-one per cent of cases showed double negativity for steroid receptors (ER-/PR-). No correlation was found between the markers and conventional parameters except for a negative correlation with the tumour grade. The high percentage of c-erbB-2 positivity and the high proportion of steroid receptor negativity suggest a need for studies on adjuvant therapy. Integration of selected markers with conventional parameters could help define subgroups for treatment and prognosis.
Asunto(s)
Neoplasias de la Mama/química , Carcinoma Intraductal no Infiltrante/química , Receptor ErbB-2/análisis , Receptores de Estrógenos/análisis , Receptores de Progesterona/análisis , Adulto , Anciano , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/química , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patología , Carcinoma Intraductal no Infiltrante/genética , Carcinoma Intraductal no Infiltrante/patología , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Trinidad y Tobago/epidemiologíaRESUMEN
One hundred and three consecutive cases of breast cancer in Trinidadian women were evaluated for steroid receptor status and c-erbB-2 receptor along with conventional parameters including age, ethnicity, tumour size, histological type and grade, and lymph node status: The molecular markers were studied by immunohistochemistry (IHC) on paraffin sections. Tumour size > 2 cm was seen in 60 of the cases. Oestrogen receptor (ER), progesterone receptor (PR) and c-erbB-2 showed 54, 46 and 63 positivity, respectively. There was no correlation between c-erbB-2 and steroid receptors. Forty-one per cent of cases showed double negativity for steroid receptors (ER-/PR-). No correlation was found between the markers and conventional parameters except for a negative correlation with the tumour grade. The high percentage of c-erbB-2 positivity and the high proportion of steroid receptor negativity suggest a need for studies on adjuvant therapy. Integration of selected markers with conventional parameters could help define subgroups for treatment and prognosis.
Asunto(s)
Humanos , Femenino , Adulto , Persona de Mediana Edad , Neoplasias de la Mama , Receptores de Progesterona , Receptor ErbB-2 , Carcinoma Intraductal no Infiltrante/química , Receptores de Estrógenos/análisis , Trinidad y Tobago , Neoplasias de la Mama , Inmunohistoquímica , Carcinoma Ductal de Mama , Carcinoma Intraductal no Infiltrante/genética , Carcinoma Intraductal no Infiltrante/patología , Biomarcadores de Tumor/análisisRESUMEN
Immunohistochemical analysis of the p53 gene protein and cytometric assessment of nuclear DNA were performed in a series of 51 cases of intraductal breast proliferation. The series included 22 cases of intraductal hyperplasia without atypia, 6 cases of intraductal hyperplasia with atypia, and 23 cases of pure intraductal carcinoma. Expression of p53 protein was detected in one case of intraductal hyperplasia without atypia (4.5 per cent), one case of intraductal hyperplasia with atypia (16.6 per cent) and six cases of intraductal carcinoma (26.0 per cent). No significant correlation was observed between p53 expression and histological subtype of intraductal carcinoma. Aneuploidy was demonstrated in two cases of intraductal hyperplasia with atypia (33.3 per cent) and in 18 cases of intraductal carcinoma (78.2 per cent). All cases of intraductal hyperplasia without atypia were euploid. No significant association was observed between p53 protein expression and ploidy in intraductal hyperplasia. The only case of intraductal hyperplasia without atypia positive for p53 was euploid, whereas the only p53-positive case of intraductal hyperplasia with atypia was aneuploid. Among the intraductal carcinomas, only the aneuploid cases showed positivity for p53, regardless of histological subtype. The results suggest that some of the changes observed in invasive breast carcinoma, such as p53 expression and aneuploidy, are already present in breast intraductal proliferation, especially in areas with atypia and in intraductal carcinoma. The expression of p53 in breast intraductal proliferation may reflect the acquisition of p53 gene mutations in cells unable adequately to repair DNA damage, with genomic instability which would lead to clonal expansion and putative evolution to invasive disease.
Asunto(s)
Neoplasias de la Mama/metabolismo , Mama/metabolismo , ADN/análisis , Lesiones Precancerosas/metabolismo , Proteína p53 Supresora de Tumor/biosíntesis , Mama/patología , Neoplasias de la Mama/genética , Carcinoma Intraductal no Infiltrante/genética , Carcinoma Intraductal no Infiltrante/metabolismo , Femenino , Humanos , Hiperplasia/metabolismo , Técnicas para Inmunoenzimas , Proteínas de Neoplasias/biosíntesis , Ploidias , Lesiones Precancerosas/genéticaRESUMEN
The establishment of a new human breast cancer cell line (IIB-BR-G) was successful after a previous growth of the cells isolated from a breast primary tumor in a female nude mouse. The IIB-BR-G cell line and the primary tumor do not express estrogen or progesterone receptors. Vimentin and keratin expression were found in the cell line and in the nude mouse tumor. This cell line displays high morphological heterogeneity with atypical multinucleated megacells, and it is capable of anchorage-independent growth and tumor formation in nude mice. The cytogenetic analysis confirmed its human origin and revealed multiple marker chromosomes and extensive chromosomal alterations including rearrangements, gains, losses, isochromosomes, and double minutes (DMs).