CINIBACentro de Investigaciones Inmunológicas Básicas y Aplicadashttps://digital.cic.gba.gob.ar/handle/11746/6147https://digital.cic.gba.gob.ar/retrieve/3d5a0b09-9f45-4665-b606-64b3ddc508a8/2024-03-28T16:49:23Z2024-03-28T16:49:23Z231A Molecular Portrait of High-Grade Ductal Carcinoma In SituAbba, Martín CarlosGong,TingLu, YueLee, JaehoZhong, YiLacunza, EzequielButti, MatíasTakata, YokoGaddis, SallyShen, JianjunEstecio, Marcos R.Sahin, Aysegul A.Aldaz, C. Marcelohttps://digital.cic.gba.gob.ar/handle/11746/61982017-09-27T13:08:39Z2015-09-01T00:00:00Zdc.type: Artículo
dcterms.isPartOf.*: vol. 75, no. 18; Cancer Research
dcterms.abstract: 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.
dcterms.publisher: AACR Publications
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dc.title: A Molecular Portrait of High-Grade Ductal Carcinoma In Situ
2015-09-01T00:00:00ZBreast Cancer Biomarker Discovery in the Functional Genomic Age: A Systematic Review of 42 Gene Expression SignaturesAbba, Martín CarlosLacunza, EzequielButti, MatíasAldaz, C. Marcelohttps://digital.cic.gba.gob.ar/handle/11746/61492017-09-14T13:42:02Z2010-10-01T00:00:00Zdc.type: Revisión
dcterms.isPartOf.*: vol. 2010, no. 5; Biomarker Insights
dcterms.abstract: In this review we provide a systematic analysis of transcriptomic signatures derived from 42 breast cancer gene expression studies, in an effort to identify the most relevant breast cancer biomarkers using a meta-analysis method. Meta-data revealed a set of 117 genes that were the most commonly affected ranging from 12% to 36% of overlap among breast cancer gene expression studies. Data mining analysis of transcripts and protein-protein interactions of these commonly modulated genes indicate three functional modules significantly affected among signatures, one module related with the response to steroid hormone stimulus, and two modules related to the cell cycle. Analysis of a publicly available gene expression data showed that the obtained meta-signature is capable of predicting overall survival (P < 0.0001) and relapse-free survival (P < 0.0001) in patients with early-stage breast carcinomas. In addition, the identified meta-signature improves breast cancer patient stratification independently of traditional prognostic factors in a multivariate Cox proportional-hazards analysis.
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dc.title: Breast Cancer Biomarker Discovery in the Functional Genomic Age: A Systematic Review of 42 Gene Expression Signatures
2010-10-01T00:00:00ZBreast cancer humoral immune response: involvement of Lewis y through the detection of circulating immune complexes and association with Mucin 1 (MUC1)Isla Larrain, Marina TeresitaDemichelis, Sandra O.Crespo, MarinaLacunza, EzequielBarbera, AlbertoCreton, AldoTerrier, FranciscoSegal-Eiras, AmadaCroce, María Virginiahttps://digital.cic.gba.gob.ar/handle/11746/37542017-12-12T15:21:11Z2009-01-01T00:00:00Zdc.type: Artículo
dcterms.isPartOf.*: vol. 28; Journal of Experimental & Clinical Cancer Research
dcterms.abstract: In cancer patients, MUC1 glycoprotein may carry Lewis y which could be involved in immune response. Purposes: 1- to evaluate the presence of Lewis y and MUC1 in circulating immune complexes (Lewis y/CIC and MUC1/CIC, respectively) and their correlation; 2- to analyze the possible presence of Lewis y in carbohydrate chains of tumoral MUC1 glycoprotein and 3- to correlate serum and tissue parameters considered. Pretreatment serum and tissue breast samples from 76 adenocarcinoma, 34 benign and 36 normal specimens were analyzed. Anti-MUC1 and anti-Lewis y MAbs were employed. To detect Lewis y/CIC and MUC1/CIC, ELISA tests were developed; serum samples containing MUC1 were previously selected by Cancer Associated Serum Antigen (CASA). Immunoprecipitation (IP) was performed in 9 malignant, benign and normal samples and analyzed by SDS-PAGE and Western blot. Lewis y and MUC1 expression was studied by immunohistochemistry (IHC). Statistical analysis was performed employing principal component analysis (PCA), ANOVA, Tukey HSD, Chi square test and classical correlation (p < 0.05). By ELISA, Lewis y/IgM/CIC levels showed statistically significant differences between breast cancer versus benign and normal samples; mean +/- SD values expressed in OD units were: 0.525 +/- 0.304; 0.968 +/- 0.482 and 0.928 +/- 0.447, for breast cancer, benign disease and normal samples, respectively, p < 0.05. Lewis y/IgG/CIC did not show any statistically significant difference. MUC1/IgM/CIC correlated with Lewis y/IgM/CIC. By CASA, 9 samples with MUC1 values above the cut off were selected and IP was performed, followed by SDS-PAGE and Western blot; bands at 200 kDa were obtained with each MAb in all the samples. By IHC, with C14 MAb, 47.5%, 31% and 35% of malignant, benign and normal samples, respectively, showed positive reaction while all the samples were positive with anti-MUC1 MAb; in both cases, with a different pattern of expression between malignant and non malignant samples. Our findings support that in breast cancer there was a limited humoral immune response through Lewis y/IgM/CIC levels detection which correlated with MUC1/IgM/CIC. We also found that Lewis y might be part of circulating MUC1 glycoform structure and also that Lewis y/CIC did not correlate with Lewis y expression.
dc.description.*: Submitted by Ariel Lira (alira@sedici.unlp.edu.ar) on 2016-07-13T21:22:35Z workflow start=Step: CIC-ADMIN_review - action:claimaction
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croce - breast cancer.pdf-PDFA.pdf: 2447415 bytes, checksum: e0d0a0dc0779f60ed1d3dcb1ed872aed (MD5)
dc.title: Breast cancer humoral immune response: involvement of Lewis y through the detection of circulating immune complexes and association with Mucin 1 (MUC1)
2009-01-01T00:00:00ZCharacterization of a P-Rex1 gene signature in breast cancer cellsBarrio Real, LauraWertheimer, EvaGarg, RachanaAbba, Martín CarlosKazanietz, Marcelo G.https://digital.cic.gba.gob.ar/handle/11746/61962017-09-27T11:49:00Z2016-01-01T00:00:00Zdc.type: Artículo
dcterms.isPartOf.*: vol. 7, no. 32; Oncotarget
dcterms.abstract: The Rac nucleotide Exchange Factor (Rac-GEF) P-Rex1 is highly expressed in breast cancer, specifically in the luminal subtype, and is an essential mediator of actin cytoskeleton reorganization and cell migratory responses induced by stimulation of ErbB and other tyrosine-kinase receptors. Heregulin (HRG), a growth factor highly expressed in mammary tumors, causes the activation of P-Rex1 and Rac1 in breast cancer cells via ErbB3, leading to a motile response. Since there is limited information about P-Rex1 downstream effectors, we carried out a microarray analysis to identify genes regulated by this Rac-GEF after stimulation of ErbB3 with HRG. In T-47D breast cancer cells, HRG treatment caused major changes in gene expression, including genes associated with motility, adhesion, invasiveness and metastasis. Silencing P-Rex1 expression from T-47D cells using RNAi altered the induction and repression of a subset of HRG-regulated genes, among them genes associated with extracellular matrix organization, migration, and chemotaxis. HRG induction of MMP10 (matrix metalloproteinase 10) was found to be highly sensitive both to P-Rex1 depletion and inhibition of Rac1 function by the GTPase Activating Protein (GAP) β2-chimaerin, suggesting the dependence of the P-Rex1/Rac1 pathway for the induction of genes critical for breast cancer invasiveness. Notably, there is a significant association in the expression of P-Rex1 and MMP10 in human luminal breast cancer, and their coexpression is indicative of poor prognosis.
Brecha entre expectativas y percepciones de los empleadores: Un aspecto importante a tener en cuenta al analizar la brecha fue considerar no sólo la evaluación actual sino también la expectativa sobre el atributo bajo análisis. En tal sentido, una brecha amplía podría deberse tanto a una buena evaluación como a una baja expectativa.
Los resultados expuestos revelaron, en concordancia con el análisis respecto de la satisfacción general de los empleadores con los graduados de la Licenciatura en Economía, que la totalidad de las brechas analizadas están dentro de la zona de satisfacción.
Las brechas de las variables con mayor expectativa sobre las competencias de los graduados referidas a cada uno de los grupos definidos, es decir, la capacidad para la identificación de problemas y encontrar la solución, la capacidad para acceder, evaluar y sintetizar información y la capacidad para pensar crítica, creativa y reflexivamente si bien no alcanzan el nivel de satisfacción total, cumplen con las expectativas de los empleadores. Adicionalmente, las brechas de las variables en las cuales los empleadores se han mostrado algo más que satisfechos fueron aquellas en las que las expectativas no eran demasiado altas al momento de realizar la encuesta.
dcterms.publisher: Impact Journals
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dc.title: Characterization of a P-Rex1 gene signature in breast cancer cells
2016-01-01T00:00:00ZDMBA induced mouse mammary tumors display high incidence of activating Pik3caH1047 and loss of function Pten mutationsAbba, Martín CarlosZhong, YiLee, JaehoKil, HyunsukLu, YueTakata, YokoSimper, Melissa S.Gaddis, SallyShen, JianjunAldaz, C. Marcelohttps://digital.cic.gba.gob.ar/handle/11746/61682017-09-19T14:38:59Z2016-08-01T00:00:00Zdc.type: Artículo
dcterms.isPartOf.*: vol. 7, no. 39; Oncotarget
dcterms.abstract: Controversy always existed on the utility of chemically induced mouse mammary carcinogenesis models as valid equivalents for the study of human breast cancer. Here, we performed whole exome and RNA sequencing on long latency mammary tumors (218 ± 27 days) induced by the carcinogen 7,12-Dimethylbenzathracene (DMBA) and short latency tumors (65 ± 11 days) induced by the progestin Medroxyprogesterone Acetate (MPA) plus DMBA in CD2F1 mice. Long latency tumors displayed a high frequency of <em>Pi3kca</em> and/or <em>Pten</em> mutations detected in 11 of 13 (85%) long latency cases (14/22, 64% overall). Eighty-two percent (9/11) of tumors carried the <em>Pik3ca</em> H1047L/R hot-spot mutation, as frequently found in human breast cancer. These tumors were luminal-like and mostly ER/PR+, as in humans. Transcriptome profiling indicated a significant activation of the PI3K-Akt pathway (p=3.82e-6). On the other hand MPA+DMBA induced short latency tumors displayed mutations in cancer drivers not commonly found mutated in human breast cancer (e.g. <em>Hras</em> and <em>Apc</em>). These tumors were mostly basal-like and MPA exposure led to <em>Rankl</em> overexpression (60 fold induction) and immunosuppressive gene expression signatures. In summary, long latency DMBA induced mouse mammary tumors reproduce the molecular profile of human luminal breast carcinomas representing an excellent preclinical model for the testing of PIK3CA/Akt/mTOR pathway inhibitory therapies and a good platform for the developing of additional preclinical tools such as syngeneic transplants in immunocompetent hosts.
dcterms.publisher: Impact Journals
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dc.title: DMBA induced mouse mammary tumors display high incidence of activating Pik3caH1047 and loss of function Pten mutations
2016-08-01T00:00:00ZEstudio del gen RHBDD2 como marcador pronóstico/predictivo frente al tratamiento neoadyuvante en el cáncer colorrectalPalma, SabinaGarcía Fabiani, María BelénAbba, Martín CarlosLacunza, Ezequielhttps://digital.cic.gba.gob.ar/handle/11746/65602018-09-26T04:02:00Z2017-10-01T00:00:00Zdc.type: Comunicacion
dcterms.isPartOf.*: vol. 7, no. 1; Tercera Época
dcterms.abstract: El cáncer colorrectal (CCR) es una enfermedad heterogénea a nivel molecular. El 5-Fluorouracilo (5-Fu) constituye la principal droga empleada como primera línea de tratamiento. En estudios previos, determinamos que el gen RHBDD2 se sobreexpresa en estadios avanzados del CCR, que se induce frente al tratamiento con 5-Fu y que se asocia al proceso de Respuesta a Estrés del Retículo Endoplasmático, fundamentalmente a la vía del UPR. El aumento de expresión de RHBDD2 en estadios avanzados del CCR y su inducción frente al 5Fu hacen del gen/proteína un target interesante a evaluar como marcador del seguimiento al tratamiento. Objetivos: evaluar en pacientes con cáncer de recto la expresión de RHBDD2 antes y después del tratamiento neoadjuvante. Establecer el efecto fenotípico de la expresión diferencial (sobreexpresión y silenciamiento) de RHBDD2 en líneas celulares de cáncer colorrectal y su comportamiento ante el tratamiento con 5-Fu.
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dc.title: Estudio del gen RHBDD2 como marcador pronóstico/predictivo frente al tratamiento neoadyuvante en el cáncer colorrectal
2017-10-01T00:00:00ZGlycerol-3-phosphate acyltransferase-2 is expressed in spermatic germ cells and incorporates arachidonic acid into triacylglycerolsCattaneo, ElizabethPellón Maisón, MagalíLacunza, EzequielColeman, Rosalind A.González Baró, María del RosarioRabassa, Martín Enriquehttps://digital.cic.gba.gob.ar/handle/11746/35072017-12-12T15:16:21Z2012-01-01T00:00:00Zdc.type: Artículo
dcterms.isPartOf.*: vol. 7, no. 8; PLoS ONE
dcterms.abstract: Background: De novo glycerolipid synthesis begins with the acylation of glycerol-3 phosphate catalyzed by glycerol-3-phosphate acyltransferase (GPAT). In mammals, at least four GPAT isoforms have been described, differing in their cell and tissue locations and sensitivity to sulfhydryl reagents. In this work we show that mitochondrial GPAT2 overexpression in CHO-K1 cells increased TAG content and both GPAT and AGPAT activities 2-fold with arachidonoyl-CoA as a substrate, indicating specificity for this fatty acid. Methods and Results: Incubation of GPAT2-transfected CHO-K1 cells with [1-14C]arachidonate for 3 h increased incorporation of [14C]arachidonate into TAG by 40%. Consistently, arachidonic acid was present in the TAG fraction of cells that overexpressed GPAT2, but not in control cells, corroborating GPAT2's role in synthesizing TAG that is rich in arachidonic acid. In rat and mouse testis, Gpat2 mRNA was expressed only in primary spermatocytes; the protein was also detected in late stages of spermatogenesis. During rat sexual maturation, both the testicular TAG content and the arachidonic acid content in the TAG fraction peaked at 30 d, matching the highest expression of Gpat2 mRNA and protein. Conclusions: These results strongly suggest that GPAT2 expression is linked to arachidonoyl-CoA incorporation into TAG in spermatogenic germ cells.
dc.description.*: Submitted by Ariel Lira (alira@sedici.unlp.edu.ar) on 2016-07-13T21:22:53Z workflow start=Step: CIC-ADMIN_review - action:claimaction
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dc.title: Glycerol-3-phosphate acyltransferase-2 is expressed in spermatic germ cells and incorporates arachidonic acid into triacylglycerols
2012-01-01T00:00:00ZInforme científico de investigador: Croce, María Virginia (2012-2014)Croce, María Virginiahttps://digital.cic.gba.gob.ar/handle/11746/3312017-12-12T15:21:46Z2014-01-01T00:00:00Zdc.type: Informe de investigador
dcterms.abstract: La diseminación tumoral constituye un complejo proceso que comprende la invasión y la metástasis o diseminación a distancia. Esta secuencia se debe a múltiples factores que incluyen marcadores tumorales del proceso, los que podrían tener utilidad clínica para el seguimiento de los pacientes con cáncer.
Durante el período informado se realizó un estudio comparado de la expresión de un conjunto de antígenos asociados a cáncer de mama en tumores primarios, metástatasis cutáneas y ganglios axilares comprometidos de la misma paciente. Se trató de establecer la existencia de una expresión diferencial de los antígenos asociados en los tres tipos de muestras analizadas.
Es un tema de especial interés el determinar los factores implicados en la diseminación tumoral a determinados órganos. En el análisis que realizamos durante este período se incluyeron los ganglios y las metástasis en piel. El cáncer de mama es el tumor primario sólido que con más frecuencia da esta localización metastásica y no se conocen los mecanismos que están implicados en esta diseminación.
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dc.title: Informe científico de investigador: Croce, María Virginia (2012-2014)
2014-01-01T00:00:00ZInforme científico de investigador: Croce, María Virginia (2014-2016)Croce, María Virginiahttps://digital.cic.gba.gob.ar/handle/11746/28282017-12-12T15:21:56Z2016-01-01T00:00:00Zdc.type: Informe de investigador
dcterms.abstract: El proceso de metástasis está regulado por el “cross-talk” entre las células neoplásicas y las del microambiente tumoral. Durante este período analizamos la identidad antigénica de las células neoplásicas en los tumores primarios y metástasis hallando diferentes subpoblaciones de células neoplásicas metastásicas que expresan MUC1, antígenos Lewis y romboides 2 justificando, al menos en parte, los posibles mecanismos de escape tumoral en relación al pronóstico de los pacientes. Se determinó la traslocación al núcleo de células neoplásicas de la fracción extramembranosa de MUC1, lo que sumaría otra vía de regulación de esta mucina a la diseminación. Asimismo, realizamos el análisis de la indoleamine-2,3-dioxygenase (IDO), molécula inmunosupresora, hallándola expresada por las células tumorales y demostrándose la asociación del gen de IDO con otros genes relacionados con la respuesta inmune y apoptosis.
Se continuó con el estudio poblacional de factores de riesgo, incidencia y prevención del cáncer de mama y el desarrollo de modelos experimentales.
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dc.title: Informe científico de investigador: Croce, María Virginia (2014-2016)
2016-01-01T00:00:00ZInforme científico de investigador: Croce, María Virginia (2016-2018)Croce, María Virginiahttps://digital.cic.gba.gob.ar/handle/11746/103122019-09-18T20:02:09Z2018-01-01T00:00:00Zdc.type: Informe de investigador
dcterms.abstract: La diseminación tumoral ocurre por la invasión de los capilares venosos y linfáticos con una primera estación en los ganglios linfáticos y posteriormente en órganos distantes.
Durante este período se estudió la expresión de moléculas de adhesión implicadas en la diseminación tumoral en tumores primarios y ganglios linfáticos de cáncer de mama y colorrectal. Se estudió la presencia de vasos sanguíneos y linfáticos de neoformación observándose la invasión de células tumorales. Se analizó la preparación de nichos metastásicos mediante la determinación de la enzima indoleamine-2,3-dioxygenase (IDO), molécula inmunomoduladora, en carcinomas mamarios primarios y ganglios linfáticos pareados y se estudió el perfil de células linfoides en los ganglios comprometidos. Asimismo, se analizó la expresión de antígenos asociados a MUC1 y su valor pronóstico en pacientes con tumores epiteliales malignos de cabeza y cuello.
Se continuó con el estudio poblacional de factores de riesgo, incidencia y prevención del cáncer de mama y el desarrollo de modelos experimentales.
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dc.title: Informe científico de investigador: Croce, María Virginia (2016-2018)
2018-01-01T00:00:00Z