MARIA MITZI BRENTANI

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Departamento de Radiologia, Faculdade de Medicina - Docente
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/05 - Laboratório de Poluição Atmosférica Experimental, Hospital das Clínicas, Faculdade de Medicina

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  • article 68 Citação(ões) na Scopus
    Comprehensive Analysis of BRCA1, BRCA2 and TP53 Germline Mutation and Tumor Characterization: A Portrait of Early-Onset Breast Cancer in Brazil
    (2013) CARRARO, Dirce Maria; FOLGUEIRA, Maria Aparecida Azevedo Koike; LISBOA, Bianca Cristina Garcia; OLIVIERI, Eloisa Helena Ribeiro; KREPISCHI, Ana Cristina Vitorino; CARVALHO, Alex Fiorini de; MOTA, Louise Danielle de Carvalho; PUGA, Renato David; MACIEL, Maria do Socorro; MICHELLI, Rodrigo Augusto Depieri; LYRA, Eduardo Carneiro de; GROSSO, Stana Helena Giorgi; SOARES, Fernando Augusto; ACHATZ, Maria Isabel Alves de Souza Waddington; BRENTANI, Helena; MOREIRA-FILHO, Carlos Alberto; BRENTANI, Maria Mitzi
    Germline mutations in BRCA1, BRCA2 and TP53 genes have been identified as one of the most important disease-causing issues in young breast cancer patients worldwide. The specific defective biological processes that trigger germline mutation-associated and -negative tumors remain unclear. To delineate an initial portrait of Brazilian early-onset breast cancer, we performed an investigation combining both germline and tumor analysis. Germline screening of the BRCA1, BRCA2, CHEK2 (c.1100delC) and TP53 genes was performed in 54 unrelated patients <35 y; their tumors were investigated with respect to transcriptional and genomic profiles as well as hormonal receptors and HER2 expression/amplification. Germline mutations were detected in 12 out of 54 patients (22%) [7 in BRCA1 (13%), 4 in BRCA2 (7%) and one in TP53 (2%) gene]. A cancer familial history was present in 31.4% of the unrelated patients, from them 43.7% were carriers for germline mutation (37.5% in BRCA1 and in 6.2% in the BRCA2 genes). Fifty percent of the unrelated patients with hormone receptor-negative tumors carried BRCA1 mutations, percentage increasing to 83% in cases with familial history of cancer. Over-representation of DNA damage-, cellular and cell cycle-related processes was detected in the up-regulated genes of BRCA1/2-associated tumors, whereas cell and embryo development-related processes were over-represented in the up-regulated genes of BRCA1/2-negative tumors, suggesting distinct mechanisms driving the tumorigenesis. An initial portrait of the early-onset breast cancer patients in Brazil was generated pointing out that hormone receptor-negative tumors and positive familial history are two major risk factors for detection of a BRCA1 germline mutation. Additionally, the data revealed molecular factors that potentially trigger the tumor development in young patients.
  • article 10 Citação(ões) na Scopus
    MicroRNAs Discriminate Familial from Sporadic Non-BRCA1/2 Breast Carcinoma Arising in Patients <= 35 Years
    (2014) BASTOS, Elen Pereira; BRENTANI, Helena; PASINI, Fatima Solange; SILVA, Aderbal Ruy T.; TORRES, Cesar Henrique; PUGA, Renato David; OLIVIERI, Eloisa Helena Ribeiro; PIOVEZANI, Amanda Rusiska; PEREIRA, Carlos Alberto de Braganca; MACHADO-LIMA, Ariane; CARRARO, Dirce Maria; BRENTANI, Maria Mitzi
    The influence of genetic factors may contribute to the poor prognosis of breast cancer (BC) at a very young age. However BRCA1/2 mutations could not explain the majority of cases arising in these patients. MicroRNAs (miRs) have been implicated in biological processes associated with BC. Therefore, we investigated differences in miRs expression between tumors from young patients (<= 35 years) with sporadic or familial history and non-carriers of BRCA1/2 mutations. Thirty-six young Brazilian patients were divided into 2 groups: sporadic (NF-BC) or familial breast cancer (F-BC). Most of the samples were classified as luminal A and B and the frequency of subtypes did not differ between familial or sporadic cases. Using real time qPCR and discriminant function analysis, we identified 9 miRs whose expression levels rather than miR identity can discriminate between both patient groups. Candidate predicted targets were determined by combining results from miRWalk algorithms with mRNA expression profiles (n = 91 differently expressed genes). MiR/mRNA integrated analysis identified 91 candidate genes showing positive or negative correlation to at least 1 of the 9 miRs. Co-expression analysis of these genes with 9 miRs indicated that 49 differentially co-expressed miR-gene interactions changes in F-BC tumors as compared to those of NF-BC tumors. Out of 49, 17 (34.6%) of predicted miR-gene interactions showed an inverse correlation suggesting that miRs act as post-transcriptional regulators, whereas 14 (28.6%) miR-gene pairs tended to be co-expressed in the same direction indicating that the effects exerted by these miRs pointed to a complex level of target regulation. The remaining 18 pairs were not predicted by our criteria suggesting involvement of other regulators. MiR-mRNA co-expression analysis allowed us to identify changes in the miR-mRNA regulation that were able to distinguish tumors from familial and sporadic young BC patients non-carriers of BRCA mutations.
  • article 17 Citação(ões) na Scopus
    Poly (A)(+) Transcriptome Assessment of ERBB2-Induced Alterations in Breast Cell Lines
    (2011) CARRARO, Dirce Maria; FERREIRA, Elisa Napolitano; MOLINA, Gustavo de Campos; PUGA, Renato David; ABRANTES, Eduardo Fernandes; TRAPE, Adriana Priscila; EKHARDT, Bedrich L.; NUNES, Diana Noronha; BRENTANI, Maria Mitzi; ARAP, Wadih; PASQUALINI, Renata; BRENTANI, Helena; DIAS-NETO, Emmanuel; BRENTANI, Ricardo Renzo
    We report the first quantitative and qualitative analysis of the poly (A)(+) transcriptome of two human mammary cell lines, differentially expressing (human epidermal growth factor receptor) an oncogene over-expressed in approximately 25% of human breast tumors. Full-length cDNA populations from the two cell lines were digested enzymatically, individually tagged according to a customized method for library construction, and simultaneously sequenced by the use of the Titanium 454-Roche-platform. Comprehensive bioinformatics analysis followed by experimental validation confirmed novel genes, splicing variants, single nucleotide polymorphisms, and gene fusions indicated by RNA-seq data from both samples. Moreover, comparative analysis showed enrichment in alternative events, especially in the exon usage category, in ERBB2 over-expressing cells, data indicating regulation of alternative splicing mediated by the oncogene. Alterations in expression levels of genes, such as LOX, ATP5L, GALNT3, and MME revealed by large-scale sequencing were confirmed between cell lines as well as in tumor specimens with different ERBB2 backgrounds. This approach was shown to be suitable for structural, quantitative, and qualitative assessment of complex transcriptomes and revealed new events mediated by ERBB2 overexpression, in addition to potential molecular targets for breast cancer that are driven by this oncogene.
  • article 6 Citação(ões) na Scopus
    A Set of miRNAs, Their Gene and Protein Targets and Stromal Genes Distinguish Early from Late Onset ER Positive Breast Cancer
    (2016) BASTOS, E. P.; BRENTANI, H.; PEREIRA, C. A. B.; POLPO, A.; LIMA, L.; PUGA, R. D.; PASINI, F. S.; OSORIO, C. A. B. T.; ROELA, R. A.; ACHATZ, M. I.; TRAPE, A. P.; GONZALEZ-ANGULO, A. M.; BRENTANI, M. M.
    Breast cancer (BC) in young adult patients (YA) has a more aggressive biological behavior and is associated with a worse prognosis than BC arising in middle aged patients (MA). We proposed that differentially expressed miRNAs could regulate genes and proteins underlying aggressive phenotypes of breast tumors in YA patients when compared to those arising in MA patients. Objective: Using integrated expression analyses of miRs, their mRNA and protein targets and stromal gene expression, we aimed to identify differentially expressed profiles between tumors from YA-BC and MA-BC. Methodology and Results: Samples of ER+ invasive ductal breast carcinomas, divided into two groups: YA-BC (35 years or less) or MA-BC (50-65 years) were evaluated. Screening for BRCA1/2 status according to the BOADICEA program indicated low risk of patients being carriers of these mutations. Aggressive characteristics were more evident in YA-BC versus MA-BC. Performing qPCR, we identified eight miRs differentially expressed (miR-9, 18b, 33b, 106a, 106b, 210, 518a-3p and miR-372) between YA-BC and MA-BC tumors with high confidence statement, which were associated with aggressive clinicopathological characteristics. The expression profiles by microarray identified 602 predicted target genes associated to proliferation, cell cycle and development biological functions. Performing RPPA, 24 target proteins differed between both groups and 21 were interconnected within a network protein-protein interactions associated with proliferation, development and metabolism pathways over represented in YA-BC. Combination of eight mRNA targets or the combination of eight target proteins defined indicators able to classify individual samples into YA-BC or MA-BC groups. Fibroblast-enriched stroma expression profile analysis resulted in 308 stromal genes differentially expressed between YA-BC and MA-BC. Conclusion: We defined a set of differentially expressed miRNAs, their mRNAs and protein targets and stromal genes that distinguish early onset from late onset ER positive breast cancers which may be involved with tumor aggressiveness of YA-BC.