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Acceso AbiertoBreast Cancer Biomarker Discovery in the Functional Genomic Age: A Systematic Review of 42 Gene Expression Signatures(2010) Abba, Martín Carlos; Lacunza, Ezequiel; Butti, Matías; Aldaz, C. MarceloIn 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.
Acceso AbiertoBreast cancer humoral immune response: involvement of Lewis y through the detection of circulating immune complexes and association with Mucin 1 (MUC1)(2009) Isla Larrain, Marina Teresita; Demichelis, Sandra O.; Crespo, Marina; Lacunza, Ezequiel; Barbera, Alberto; Creton, Aldo; Terrier, Francisco; Segal-Eiras, Amada; Croce, María VirginiaIn 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.
Acceso AbiertoCharacterization of a P-Rex1 gene signature in breast cancer cells(Impact Journals, 2016) Barrio Real, Laura; Wertheimer, Eva; Garg, Rachana; Abba, Martín Carlos; Kazanietz, Marcelo G.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.
Acceso AbiertoDMBA induced mouse mammary tumors display high incidence of activating Pik3caH1047 and loss of function Pten mutations(Impact Journals, 2016) Abba, Martín Carlos; Zhong, Yi; Lee, Jaeho; Kil, Hyunsuk; Lu, Yue; Takata, Yoko; Simper, Melissa S.; Gaddis, Sally; Shen, Jianjun; Aldaz, C. MarceloControversy 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 Pi3kca and/or Pten mutations detected in 11 of 13 (85%) long latency cases (14/22, 64% overall). Eighty-two percent (9/11) of tumors carried the Pik3ca 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. Hras and Apc). These tumors were mostly basal-like and MPA exposure led to Rankl 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.
Acceso AbiertoEstudio del gen RHBDD2 como marcador pronóstico/predictivo frente al tratamiento neoadyuvante en el cáncer colorrectal(2017) Palma, Sabina; García Fabiani, María Belén; Abba, Martín Carlos; Lacunza, EzequielEl 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.
Acceso AbiertoGlycerol-3-phosphate acyltransferase-2 is expressed in spermatic germ cells and incorporates arachidonic acid into triacylglycerols(2012) Cattaneo, Elizabeth; Pellón Maisón, Magalí; Lacunza, Ezequiel; Coleman, Rosalind A.; González Baró, María del Rosario; Rabassa, Martín EnriqueBackground: 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.
Acceso AbiertoThe head and neck cancer cell oncogenome: a platform for the development of precision molecular therapies(Impact Journals, 2014) Martin, Daniel; Abba, Martín Carlos; Molinolo, Alfredo A.; Vitale-Cross, Lynn; Wang, Zhiyong; Zaida, Moraima; Delic, Naomi C.; Samuels, Yardena; Lyons, J. Guy; Gutkind, J. SilvioThe recent elucidation of the genomic landscape of head and neck squamous cell carcinoma (HNSCC) has provided a unique opportunity to develop selective cancer treatment options. These efforts will require the establishment of relevant HNSCC models for preclinical testing. Here, we performed full exome and transcriptome sequencing of a large panel of HNSCC-derived cells from different anatomical locations and human papillomavirus (HPV) infection status. These cells exhibit typical mutations in TP53, FAT1, CDK2NA, CASP8, and NOTCH1, and copy number variations (CNVs) and mutations in PIK3CA, HRAS, and PTEN that reflect the widespread activation of the PI3K-mTOR pathway. SMAD4 alterations were observed that may explain the decreased tumor suppressive effect of TGF-β in HNSCC. Surprisingly, we identified HPV+ HNSCC cells harboring TP53 mutations, and documented aberrant TP53 expression in a subset of HPV+ HNSCC cases. This analysis also revealed that most HNSCC cells harbor multiple mutations and CNVs in epigenetic modifiers (e.g., EP300, CREBP, MLL1, MLL2, MLL3, KDM6A, and KDM6B) that may contribute to HNSCC initiation and progression. These genetically-defined experimental HNSCC cellular systems, together with the identification of novel actionable molecular targets, may now facilitate the pre-clinical evaluation of emerging therapeutic agents in tumors exhibiting each precise genomic alteration.
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Acceso AbiertoMetástasis cutáneas de cáncer de mama(2018) Croce, María Virginia; Castro Luna Berenguer, Ana María Del Carmen; Isla Larrain, Marina Teresita; Rabassa, Martín Enrique; Cabaleiro, P.; Zwenger, A. O.; Canzoneri, R.; Abba, Martín Carlos; Segal Eiras, AmadaEl objetivo de este estudio es identificar perfiles correspondientes a la metástasis cutánea en el cáncer de mama mediante el análisis de marcadores tumorales tales como MUC1 y antígenos carbohidratos asociados.
Acceso AbiertoA Molecular Portrait of High-Grade Ductal Carcinoma In Situ(AACR Publications, 2015) Abba, Martín Carlos; Gong,Ting; Lu, Yue; Lee, Jaeho; Zhong, Yi; Lacunza, Ezequiel; Butti, Matías; Takata, Yoko; Gaddis, Sally; Shen, Jianjun; Estecio, Marcos R.; Sahin, Aysegul A.; Aldaz, C. MarceloDuctal 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.
Acceso AbiertoMUCI expression and anti-MUCI serum immune response in head and neck squamous cell carcinoma (HNSCC): A multivariate analysis(2006) Pereyra, Adrián; Segal-Eiras, Amada; Croce, María Virginia; Rabassa, Martín EnriqueBackground: HNSCC progression to adjacent tissue and nodes may be mediated by altered glycoproteins and glycolipids such as MUC1 mucin. This report constitutes a detailed statistical study about MUC1 expression and anti-MUC1 immune responses in relation to different clinical and pathological parameters which may be useful to develop new anti HNSCC therapeutic strategies. Patients and methods: Fifty three pre treatment HNSCC patients were included: 26 (49.1%) bearing oral cavity tumors, 17 (32.1%) localized in the larynx and 10 (18.8%) in the pharynx. Three patients (5.7%) were at stage I, 5 (9.4%) stage II, 15 (28.3%) stage III and 30 (56.6%) at stage IV. MUC1 tumor expression was studied by immunohistochemistry employing two anti-MUC1 antibodies: CT33, anti cytoplasmic tail MUC1 polyclonal antibody (Ab) and C595 anti-peptidic core MUC1 monoclonal antibody. Serum levels of MUC1 and free anti-MUC1 antibodies were detected by ELISA and circulating immune complexes (CIC) by precipitation in polyethylene glycol (PEG) 3.5%; MUC1 isolation from circulating immune complexes was performed by protein A-sepharose CL-4B affinity chromatography followed by SDS-PAGE and Western blot. Statistical analysis consisted in Multivariate Principal Component Analysis (PCA); ANOVA test (Tukey's test) was employed to find differences among groups; nonparametrical correlations (Kendall's Tau) were applied when necessary. Statistical significance was set to p < 0.05 in all cases. Results: MUC1 cytoplasmic tail was detected in 40/50 (80%) and MUC1 protein core in 9/50 (18%) samples while serum MUC1 levels were elevated in 8/53 (15%) patients. A significant statistical correlation was found between MUC1 serum levels and anti-MUC1 IgG free antibodies, while a negative correlation between MUC1 serum levels and anti-MUC1 IgM free antibodies was found. Circulating immune complexes were elevated in 16/53 (30%) samples and were also statistically associated with advanced tumor stage. MUC1 was identified as an antigenic component of IgG circulating immune complexes. Moreover, poorly differentiated tumors were inversely correlated with tumor and serum MUC1 detection and positively correlated with node involvement and tumor mass. Conclusion: Possibly, tumor cells produce MUC1 mucin which is liberated to the circulation and captured by IgG antibodies forming MUC1-IgG-CIC. Another interesting conclusion is that poorly differentiated tumors are inversely correlated with tumor and serum MUC1 detection.
Acceso AbiertoProtein kinase C and cancer: what we know and what we do not(2014) Garg, Rachana; Benedetti, Lorena G.; Abera, Mahlet B.; Wang, HongBin; Abba, Martín Carlos; Kazanietz, Marcelo G.Since their discovery in the late 1970’s, protein kinase C (PKC) isozymes represent one of the most extensively studied signaling kinases. PKCs signal through multiple pathways and control the expression of genes relevant for cell cycle progression, tumorigenesis and metastatic dissemination. Despite the vast amount of information concerning the mechanisms that control PKC activation and function in cellular models, the relevance of individual PKC isozymes in the progression of human cancer is still a matter of controversy. Although the expression of PKC isozymes is altered in multiple cancer types, the causal relationship between such changes and the initiation and progression of the disease remains poorly defined. Animal models developed in the last years helped to better understand the involvement of individual PKCs in various cancer types and in the context of specific oncogenic alterations. Unraveling the enormous complexity in the mechanisms by which PKC isozymes impact on tumorigenesis and metastasis is key for reassessing their potential as pharmacological targets for cancer treatment.
Acceso AbiertoRhomboid domain containing 2 (RHBDD2): A novel cancer-related gene over-expressed in breast cancer(2009) Abba, Martín Carlos; Lacunza, Ezequiel; Nunez, M. I.; Colussi, Andrea G.; Isla Larrain, Marina Teresita; Segal Eiras, Amada; Croce, María Virginia; Aldaz, C. MarceloIn the course of breast cancer global gene expression studies, we identified an uncharacterized gene known as RHBDD2 (Rhomboid domain containing 2) to be markedly over-expressed in primary tumors from patients with recurrent disease. In this study, we identified RHBDD2 mRNA and protein expression significantly elevated in breast carcinomas compared with normal breast samples as analyzed by SAGE (n=46) and immunohistochemistry (n=213). Interestingly, specimens displaying RHBDD2 over-expression were predominantly advanced stage III breast carcinomas (p=0.001). Western-blot, RT-PCR and cDNA sequencing analyses allowed us to identify two RHBDD2 alternatively spliced mRNA isoforms expressed in breast cancer cell lines. We further investigated the occurrence and frequency of gene amplification and over-expression affecting RHBDD2 in 131 breast samples. RHBDD2 gene amplification was detected in 21% of 98 invasive breast carcinomas analyzed. However, no RHBDD2 amplification was detected in normal breast tissues (n=17) or breast benign lesions (n=16) (p=0.014). Interestingly, siRNA mediated silencing of RHBDD2 expression results in a decrease of MCF7 breast cancer cells proliferation compared with the corresponding controls (p=0.001). In addition, analysis of publicly available gene expression data showed a strong association between high RHBDD2 expression and decreased overall survival (p=0.0023), relapsefree survival (p= 0.0013), and metastasis-free interval (p=0.006) in patients with primary ERnegative breast carcinomas. In conclusion, our findings suggest that RHBDD2 over-expression behaves as an indicator of poor prognosis and may play a role facilitating breast cancer progression.